HPV-Mediated Radiosensitivity in Oropharyngeal Squamous Cell Carcinoma: Molecular Mechanisms and Cellular Pathways

While the oncogenic potential of HPV has been well-established in other disease sites (e.g. cervix, vulva, anus), it is increasingly evident that a significant proportion of oropharyngeal cancer cases are related to the virus. Although considerable progress has been made in the understanding of this disease with respect to its underlying biology and clinical behavior, numerous questions persist. From a therapeutic standpoint, HPV-positive oropharyngeal cancer has been shown to be more radiosensitive than HPV-negative disease. However, how HPV mediates this radiosensitivity is relatively uncertain.

Given that it has been firmly established that patients with HPV-positive oropharyngeal cancer have a significantly improved prognosis as a result of their exquisite response to radiation and can be treated with less-than-standard doses, logical questions pertain to how HPV confers this benefit to infected patients. Although the exact reason for the improved radiosensitivity of HPV-positive oropharyngeal carcinoma is unclear, multiple theories have been proposed. Indeed, it is likely that no single explanation exists for the increased radiosensitivity, and instead, HPV likely exerts its influence through a cascade of activated pathways at both the cellular level and tumor microenvironment. As will be discussed in this review, the proposed mechanisms for HPV-induced radiation response have generally centered on the disruption of such cellular pathways as DNA repair, cell cycle checkpoints, metabolic-induced stress, immunology, and cancer stem cells. Given that HPV-positive oropharyngeal cancer is increasingly recognized as a public health problem, the search to better understand its unique biological radiosensitivity has important societal and treatment-related implications.