The Balance between Differentiation and Terminal Differentiation Maintains Oral Epithelial Homeostasis

SIMPLE SUMMARY: Oral cancer affecting the oral cavity represents the most common cancer of the head and neck region. Oral cancer develops in a multistep process in which normal cells gradually accumulate genetic and epigenetic modifications to evolve into a malignant disease. Mortality for oral cancer patients is high and morbidity has a significant long-term impact on the health and wellbeing of affected individuals, typically resulting in facial disfigurement and a loss of the ability to speak, chew, taste, and swallow. The limited scope to which current treatments are able to control oral cancer underlines the need for novel therapeutic strategies. This review highlights the molecular differences between oral cell proliferation, differentiation and terminal differentiation, defines terminal differentiation as an important tumour suppressive mechanism and establishes a rationale for clinical investigation of differentiation-paired therapies that may improve outcomes in oral cancer. ABSTRACT: The oral epithelium is one of the fastest repairing and continuously renewing tissues. Stem cell activation within the basal layer of the oral epithelium fuels the rapid proliferation of multipotent progenitors. Stem cells first undergo asymmetric cell division that requires tightly controlled and orchestrated differentiation networks to maintain the pool of stem cells while producing progenitors fated for differentiation. Rapidly expanding progenitors subsequently commit to advanced differentiation programs towards terminal differentiation, a process that regulates the structural integrity and homeostasis of the oral epithelium. Therefore, the balance between differentiation and terminal differentiation of stem cells and their progeny ensures progenitors commitment to terminal differentiation and prevents epithelial transformation and oral squamous cell carcinoma (OSCC). A recent comprehensive molecular characterization of OSCC revealed that a disruption of terminal differentiation factors is indeed a common OSCC event and is superior to oncogenic activation. Here, we discuss the role of differentiation and terminal differentiation in maintaining oral epithelial homeostasis and define terminal differentiation as a critical tumour suppressive mechanism. We further highlight factors with crucial terminal differentiation functions and detail the underlying consequences of their loss. Switching on terminal differentiation in differentiated progenitors is likely to represent an extremely promising novel avenue that may improve therapeutic interventions against OSCC.