HPV, hypoxia and radiation response in head and neck cancer

Abstract

Over the last decades, the incidence of human papilloma virus (HPV) positive head and neck squamous-cell carcinoma (HNSCC) has significantly increased. Infection with high-risk HPV types drives tumourigenesis through expression of the oncoproteins E6 and E7. Currently, the primary treatment of HNSCC consists of radiotherapy, often combined with platinum-based chemotherapeutics. One of the common features of HNSCC is the occurrence of tumour hypoxia, which impairs the efficacy of radiotherapy and is a negative prognostic factor. Therefore, it is important to detect and quantify the severity of hypoxia, as well as develop strategies to specifically target hypoxic tumours. HPV-positive tumours are remarkably radiosensitive compared to HPV-negative tumours and consequently the HPV-positive patients have a better prognosis. This provides an opportunity to elucidate mechanisms of radiation sensitivity, which may reveal targets for improved therapy for HPV-negative head and neck cancers. In this review, we will discuss the differences between HPV-positive and HPV-negative head and neck tumours and methods of hypoxia detection and targeting in these disease types. Particular emphasis will be placed on the mechanisms by which HPV infection impacts radiosensitivity.

Figure 1.

Overview of the key characteristics of HPV-positive and HPV-negative HNSCC can be divided into HPV-positive and HPV-negative subgroups, with each having unique characteristics. Overall, patients with HPV-positive tumours have a better prognosis and are more radiosensitive. The overall mutation rate and frequency of p53 mutations is higher in HPV-negative tumours. Despite their different aetiology, both HPV-negative and HPV-positive tumours display a similar degree of hypoxia. HNSCC, head and neck squamous-cell carcinoma; HPV, human papilloma virus; TME, tumour microenvironment.

Figure 2.

Mechanisms contributing to an altered DDR and increased radiosensitivity in HPV-positive HNSCC Infection with HPV, and subsequent expression of E6 and E7, contribute to an altered DDR in HNSCC tumour cells. E6, E7, and possibly other un-described mechanisms, repress DNA damage signalling transducers and effectors, such as SMG-1, p53, and BRCA2. Irradiation of HPV-positive tumour cells causes significantly more yH2AX and RAD51 foci than in HPV-negative tumour cells. Additionally, it is believed that HPV-positive tumour cells have a delay in DSB repair, as measured by 53BP1 foci clearance, indicating that HPV-positive tumour cells have impaired DSB repair mechanisms, contributing to their intrinsic radiosensitivity. DDR, DNA damage response; DSB, double strand breaks; HNSCC, head and neck squamous-cell carcinoma; HPV, human papilloma virus.