Areca-treated fibroblasts enhance tumorigenesis of oral epithelial cells

• Main Authors: Hsuan-Hsuan Lu, 呂萱萱
• Other Authors: Kuo-Wei Chang
• Format: Others
• Language: en_US
• Published: 2008
• Online Access: http://ndltd.ncl.edu.tw/handle/mngan5

博士 === 國立陽明大學 === 口腔生物研究所 === 97 === Several hundred million Asians chew areca nut, which is highly associated with the oral carcinogenesis in people of this region. The impacts of areca nut extract (ANE) on oral target cells are largely unclear. Areca nut chewing is associated with an increase in the incidence of oral neoplastic or inflammatory diseases. Aberrations in matrix metalloprotease (MMP) expression are associated with the pathogenesis of oral diseases. This study investigated the potential effects of ANE on human oral fibroblasts and the consequential impacts on pathogenesis. This study hypothesized an inductive role of areca nut-exposed stromal cells in the progression of oral carcinomas. Chronic subtoxic (less than 10 μg/ml) ANE treatment resulted in premature growth arrest, the appearance of senescence-associated β-galactosidase activity and various other senescence-associated phenotypes in oral fibroblasts. Oral fibroblasts established from older individuals had a higher propensity to become ANE-induced senescent oral fibroblasts (ASOF). An activation of MMP-2 was identified in ASOF. The supernatants of ASOF activated AKT signaling pathway in oral carcinoma cells. The enhancement of proliferation, migration and anchorage-independent growth of oral carcinoma cells elicited by such supernatants can be abolished by blockers against MMP-2 or AKT. Subcutaneous co-injection of ASOF into nude mice significantly enhanced the tumorigenecity of xenographic oral carcinoma cells. The supernatants also enhanced the invasion of neutrophil in an in vitro model. This study concludes that ANE may impair oral fibroblasts and then modulate the microenvironment that dives the progression of oral epithelial oncogenesis via their secreted molecules, such as MMP-2.