TNFα Signaling Is Increased in Progressing Oral Potentially Malignant Disorders and Regulates Malignant Transformation in an Oral Carcinogenesis Model

Frontiers in Oncology

Jeffrey W. Chadwick¹  Michael Glogauer¹  Marco A. Magalhaes²  Aiman A. Ali³  Rachel Macdonald³ 

[1] Department of Dental Oncology and Maxillofacial Prosthetics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada;Department of Dentistry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada;Faculty of Dentistry, University of Toronto, Toronto, ON, Canada;

关键词: carcinogenesis;    squamous cell carcinoma;    dysplasia;    neutrophils;    inflammation;    TNFa;   

DOI  :  10.3389/fonc.2021.741013

来源: DOAJ

【 摘 要 】

Oral carcinogenesis represents a multi-stage process which encompasses several genetic and molecular changes that promote the progression of oral potentially malignant disorders (OPMDs) to oral squamous cell carcinomas (OSCCs). A better understanding of critical pathways governing the progression of OMPDs to OSCCs is critical to improve oncologic outcomes in the future. Previous studies have identified an important role of tumor necrosis factor α (TNFα) and TNF receptor 1 (TNFR1) in the invasiveness of oral cancer cell lines. Here, we investigate the expression of TNFα and TNFR1 in human OPMDs that progress to OSCC compared to non-progressing OPMDs utilizing fluorescent immunohistochemistry (FIHC) to show increased TNFα/TNFR1 expression in progressing OPMDs. In order to interrogate the TNFα/TNFR1 signaling pathway, we utilized a 4-nitroquinoline 1-oxide (4-NQO) mouse model of oral carcinogenesis to demonstrate that TNFα/TNFR1 expression is upregulated in 4-NQO-induced OSCCs. TNFα neutralization decreased serum cytokines, inhibited the development of invasive lesions and reduced tumor-associated neutrophils in vivo. Combined, this data supports the role of TNFα in oral malignant transformation, suggesting that critical immunoregulatory events occur downstream of TNFR1 leading to malignant transformation. Our results advance the understanding of the mechanisms governing OSCC invasion and may serve as a basis for alternative diagnostic and therapeutic approaches to OPMDs and OSCC management.

【 授权许可】

Unknown