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.

Nerve Growth Factor (NGF)—Receptor Survival Axis in Head and Neck Squamous Cell Carcinoma

“…In HNSCC, the HPV-carcinogenesis has been published to contribute to preferred patient survival [ 25 , 26 ] compared to HPV-negative background, which has been confirmed by our data as well. The HPV carcinogenesis background did not show any relation with NGF gene expression or with IHC detection of NGF receptors.…”

“…A significant effect has been seen in HPV-negative cases, when p75NTR high staining was accompanied by high NTRK1 staining in the tumor cell nests, which was related with significantly lower patient survival compared with cases where both p75NTR and NTRK1 were low or not present, or only one of them was present. These data suggest that the positive HPV detection is related with patient survival benefit, as confirmed by the current data and by published references [ 25 , 26 ], and it is at the moment the strongest considerable patient survival influencing factor in HNSCC. In HPV + cases the neurotrophin receptors were not related with significant survival effects.…”

“…The NTRK1 and p75NTR staining levels were not related to significant patient survival effects in Kaplan–Meier censored case survival processing where Log Rank (Mantel–Cox) pairwise comparisons were performed ( Appendix B ; Table A1 ), if all cases were processed. Because of the strong beneficial survival influence of HPV-background [ 25 , 26 ], HPV-positive and -negative cases were also separately processed, to eliminate the major survival influence of the HPV background. Indeed, 90% of HPV-positive patients with wild type TP53 survived two years after first contact, while 50% HPV-negative patients with altered p53 were lost within two years after first contact (own unpublished data, Log Rank (Mantel–Cox) pairwise comparison; p < 10 −3 ).…”

“…The development of HNSCC is related to tobacco use and alcohol consumption, as the most identified risk factors, but human papilloma virus (HPV), a sexually transmitted infection, has increasing significance as another primary cause of HNSCC [ 24 ]. HPV-positive tumors not only have a different etiology, but they also remarkably better respond to radio(chemo)therapy [ 25 ], as well as surgery [ 26 ], compared to HPV-negative tumors. Concluding, the HPV-positive patients have a better prognosis.…”

Synergistic effect of cisplatin chemotherapy combined with fractionated radiotherapy regimen in HPV-positive and HPV-negative experimental pharyngeal squamous cell carcinoma

“…It has been suggested that this www.nature.com/scientificreports www.nature.com/scientificreports/ effect is due to impaired DNA repair mechanisms, cell cycle dysregulation and increased levels of reactive oxygen species, caused mainly by HPV-related proteins E6 and E7. In fact, E6 protein binds to the p53 protein, and E7 binds to the Retinoblastoma (Rb) protein, which both mediate proteasomal degradation of targeted proteins and consequently abrogate apoptosis and senescence in host cells or arrest cells in G 2 /M phase, which is the most vulnerable to irradiation 4,8,[31][32][33] . Furthermore, irradiation of HPV-positive cells induces fast progression of cells through S phase with subsequent arrest in G 2 /M phase 4,6,8 .…”