Contribution of Notch Signaling to Chronic Radiation-Induced Salivary Gland Damage

Radiation treatment of head and neck cancer results in severe and chronic salivary gland dysfunction in most individuals. Ionizing radiation (IR)-induced injury to salivary glands stimulates a wound healing response that involves compensatory proliferation; however the mechanisms regulating this process are unclear. Objective: To delineate the molecular pathways involved in chronic IR-induced dysfunction in order to discover new restorative therapeutic interventions.  Methods: Mice were exposed to targeted head and neck radiation and salivary glands were evaluated biochemically and histologically. Results: We show that the number of p63-positive cells in irradiated salivary glands increases within 9 days and is sustained for at least 30 days. Because p63 is known to mark epithelial progenitors, this indicates a gain in undifferentiated cells. Transcription of the Notch ligands Jagged1 and Jagged2 has been shown to be downstream of p63 and are elevated in irradiated salivary glands. Consistent with this observation, Notch1 signaling is activated within 6 days, and a similar increase in the transcriptional repressors Snail and Slug are seen. Our hypothesis is that radiation induces compensatory proliferation in salivary glands, but that these proliferative cells fail to fully differentiate due to inhibition of E-cadherin by Snail. Conclusion: We speculate that without a signal to differentiate, radiation-induced damage is never fully repaired, leading to chronic loss of function. Understanding the events that control this process may allow us to design therapies to induce differentiation and concomitant regeneration in irradiated salivary glands.