Concurrent transient activation of Wnt/-catenin pathway prevents radiation damage to salivary glands.
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PURPOSE: Many head and neck cancer survivors treated with radiotherapy suffer from permanent impairment of their salivary gland function, for which few effective prevention or treatment options are available. This study explored the potential of transient activation of Wnt/-catenin signaling in preventing radiation damage to salivary glands in a preclinical model. METHODS AND MATERIALS: Wnt reporter transgenic mice were exposed to 15 Gy single-dose radiation in the head and neck area to evaluate the effects of radiation on Wnt activity in salivary glands. Transient Wnt1 overexpression in basal epithelia was induced in inducible Wnt1 transgenic mice before together with, after, or without local radiation, and then saliva flow rate, histology, apoptosis, proliferation, stem cell activity, and mRNA expression were evaluated. RESULTS: Radiation damage did not significantly affect activity of Wnt/-catenin pathway as physical damage did. Transient expression of Wnt1 in basal epithelia significantly activated the Wnt/-catenin pathway in submandibular glands of male mice but not in those of females. Concurrent transient activation of the Wnt pathway prevented chronic salivary gland dysfunction following radiation by suppressing apoptosis and preserving functional salivary stem/progenitor cells. In contrast, Wnt activation 3 days before or after irradiation did not show significant beneficial effects, mainly due to failure to inhibit acute apoptosis after radiation. Excessive Wnt activation before radiation failed to inhibit apoptosis, likely due to extensive induction of mitosis and up-regulation of proapoptosis gene PUMA while that after radiation might miss the critical treatment window. CONCLUSION: These results suggest that concurrent transient activation of the Wnt/-catenin pathway could prevent radiation-induced salivary gland dysfunction.
