TLR4 Expression in Ex-Lichenoid Lesions-Oral Squamous Cell Carcinomas and Its Surrounding Epithelium: The Role of Tumor Inflammatory Microenvironment.

Fernanda Visioli,Vito Rodolico,Maria Carmela Pedicillo,Rosalia Leonardi,Giuseppe Pannone,Ilenia Sara De Stefano,Margherita Cerrone,Monica Cantile,Nunzia Simona Losito,Gian Franco Zannoni,Angela Santoro,Giuseppe Colella,Gabriella Aquino,Giuseppina Campisi,Lorenzo Lo Muzio,Julia Silveira Nunes,Marco Visconti,Cristina Pizzulli,Maria Antonietta Ramunno

doi:10.3390/biom12030385

Abstract

Toll-like receptors (TLRs) regulate innate and adaptive immune responses. Moreover, TLRs can induce a pro-survival and pro-proliferation response in tumor cells. This study aims to investigate the expression of TLR4 in the epithelium surrounding oral squamous cell carcinomas (OSCC) in relation to its inflammatory microenvironment. This study included 150 human samples: 30 normal oral control (NOC), 38 non-lichenoid epithelium surrounding OSCC (NLE-OSCC), 28 lichenoid epithelium surrounding OSCC (LE-OSCC), 30 OSCC ex-non oral lichenoid lesion (OSCC Ex-NOLL), and 24 OSCC ex-oral lichenoid lesion (OSCC Ex-OLL). TLR4 expression was investigated by immunohistochemistry and the percentage of positive cells was quantified. In addition, a semiquantitative analysis of staining intensity was performed. Immunohistochemical analysis revealed that TLR4 is strongly upregulated in LE-OSCC as compared to normal control epithelium and NLE-OSCC. TLR4 expression was associated with the inflammatory environment, since the percentage of positive cells increases from NOC and NLE-OSCC to LE-OSCC, reaching the highest value in OSCC Ex–OLL. TLR4 was detected in the basal third of the epithelium in NLE-OSCC, while in LE-OSCC, TLR4 expression reached the intermediate layer. These results demonstrated that an inflammatory microenvironment can upregulate TLR4, which may boost tumor development.

Highlights

Immunohistochemical analysis revealed that TLR4 is strongly upregulated in nontumoral epithelial surrounding oral squamous cell carcinomas (OSCC) (Figure 1) compared to normal control epithelium, as well as in OSCC cells (Figure 2)
An increase immunoexpression was observed from normal oral mucosa to the epithelium surrounding noexpression was observed from normal oral mucosa to the epithelium surrou
Our results demonstrate TLR4 upregulation in OSCC, which can be associated with the cancer inflammatory microenvironment, since its expression increases when a lichenoid infiltrate surrounds the tumor

Summary

Introduction

Oral and pharyngeal cancer represent the sixth most common cancers in the world; an estimated 354,900 new cases and 177,400 deaths from oral cavity cancer (including lip cancer) occurred in 2018 worldwide [1]. The important role of the tumor microenvironment (TME) in the progression of cancer has become increasingly evident. OSCC may arise in an immune cell-rich environment, where inflammatory cells within TME may produce both pro-cancerogenic and anti-cancerogenic effects [3]. The immune response was thought to act only as an anti-tumor mechanism, as an attempt to prevent cancer progression. Inflammation in the early stages of carcinogenesis can boost the cancer development [6,7]. This is important regarding potentially malignant disorders associated with chronic inflammation and immune activation, such as oral lichen planus and oral lichenoid lesions [8]. Oral lichenoid lesion (OLL) is a term used to diagnose white and/or red, unilateral or bilateral lesions which cannot be characterized as oral lichen planus. OLL presents an intense inflammatory infiltrate underlying epithelial tissue, which can be deeper and extend beyond the epithelial-connective tissue interface [9]

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