Abstract 4204: Essential role of odontoblastic Smad4 in suppressing multiple keratocystic odontogenic tumors in mice

Abstract

Abstract Keratocystic odontogenic tumors (KCOT) are cystic epithelial neoplasias with a high recurrence rate. However, the molecular mechanisms underlying the initiation and progression of KCOTs are still largely unknown. Here, we show that specific ablation of Smad4 in odontoblasts unexpectedly resulted in spontaneous KCOTs in mice. The mutant mice exhibited malformed teeth characterized by fractured incisors and truncated molar roots. These abnormalities were mainly caused by disrupted odontoblast differentiation that led to irregular dentin formation. The cystic tumors arising from the reactivation of epithelial rests of Malassez (ERM), in which Smad4 remained intact, proliferated and formed stratified and differentiated squamous epithelia which exhibited a dramatic up-regulation of Hedgehog signaling. Odontoblasts which are responsive to TGF-β/BMP signals may produce signal molecules to inhibit the activation of ERM. Indeed, we observed a down-regulation of BMP signals from Smad4 mutant odontoblasts to adjacent Hertwig's epithelial root sheath (HERS). Intriguingly, KCOTs frequently emerged from Smad4-deficient ERMs in the keratinocyte specific Smad4 knockout mice, suggesting a novel mechanism that reciprocal TGF-β/BMP signaling between odontoblasts and HERS were required for tooth root development and suppression of KCOT formation. These findings provide insight into the genetic basis underlying KCOTs and important implications for new directions in KCOT treatments. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4204.