Tissue reactions to ionizing radiation-Oral mucosa

Radiotherapy is one of the most effective treatment strategies for solid malignancies, including head-and-neck tumors (HNT). Oral mucositis is the most frequent, often dose-limiting early adverse event of radio(chemo)therapy for HNT. The oral mucosal response is - like that of typical turnover tissues - based on radiation-induced impairment of epithelial proliferation and cell production, in face of ongoing physiological cell differentiation and cell loss, consequently resulting in hypoplasia and eventually mucosal ulceration. The regenerative epithelial response, i.e. repopulation, and hence the impact of overall treatment time, besides intrinsic radiosensitivity, is the dominant parameter of the radiation tolerance of oral mucosa in fractionated radiotherapy protocols. The epithelial changes are accompanied, at the molecular and cellular level, by various changes in non-epithelial cell populations, i.e. vascular endothelial cells, macrophages, and fibroblasts. An inflammatory response precedes and parallels the epithelial changes; this includes vasodilation associated with rheological consequences and the manifestation of local hypoxia, activation of macrophages and endothelial cells. During these processes, a variety of intra- and intercellular communication pathways are modulated; NF-κB associated signaling is one prominent example. The interactions of these extra-epithelial changes with epithelial hypoplasia, ulceration and regeneration currently remain largely unclear. Research on the molecular mechanisms underlying the clinical manifestation of oral mucositis will allow for identification of potential early biomarkers of oral mucosal morbidity and thus for individualization of patient follow-up and treatment, and also for the development of targeted strategies for prophylaxis and/or mitigation of oral mucositis. This review summarizes the features of the clinical manifestation of oral mucositis and its consequences, the "classical" radiobiological parameters of mucosal radiation sensitivity. It moreover focuses on the underlying "molecular" mechanisms, and on biology-based approaches for the amelioration of radiation-induced oral mucositis.