Studies have identified subpopulations of cells within tumors that drive tumor growth and recurrence, termed cancer stem-like cells (CSCs). CSCs are resistant to many current cancer treatments, including chemo- and radiation therapy. This suggests that many cancer therapies, while killing the bulk of tumor cells, may ultimately fail because they do not eliminate CSCs, which survive to regenerate new tumors. However, since CSCs generally comprise only small minorities within cancer cell populations, standard high-throughput cell viability assays applied to bulk populations of cancer cells cannot identify agents with CSC-specific toxicity. The induction of an epithelial-mesenchymal transition (EMT) in normal or neoplastic mammary epithelial cell populations has been shown to result in the enrichment of cells with stem-like properties. Therefore, we sought to increase the proportion of CSCs in oral cancer cell populations by inducing through an EMT. To this end, we modified experimentally transformed FaDu oral cancer cells by the human TWIST1 gene, which represses E-cadherin. Our preliminary data demonstrated that overexpression of TWIST1 in FaDu oral cancer cells were essential for tumour-initiating capability and drug resistant. We exploited this observation to develop and implement a screening method to identify agents with specific toxicity for oral CSCs. Our preliminary data suggest that emodin was identified as selective inhibitors of immortalized human oral cancer cells (FaDu-twist1) that had undergone an EMT. In this program, we will use all established measures of CSC activity to test whether FaDu-twist1 cell populations that had undergone an EMT contained a significantly greater proportion of CSCs relative to control cell populations. We next examine whether oral cancer cell populations that have been experimentally induced into EMT also share this aspect of CSC biology, namely an increased resistance to chemotherapeutic drugs. Moreover, the objectives of this program are to examine the molecular mechanisms by which emodin inhibits stem cell characteristics and overcome chemotherapeutic drugs resistance of oral CSCs. Finally, we plan to assess the specific effects of emodin in vivo in the FaDu or FsDu/twist1 orthotopic xenograft model.
