No abstract

One emerging concept of the development of drug-resistant tumors involves a pool of self-renewing malignant progenitors. However, the factors and molecular mechanisms that govern this process remain largely elusive. It has been reported that the high malignancy of these cells is associated with a more efficient cytokine network. In this study, we characterized tumor-initiating cells (TIC) from human ovarian cancer cell line as a model. In contrast to non-TIC, TIC had higher colony formation ability in vitro and greater tumorigenicity in vivo, suggesting that TIC enrich cancer stem-like cells. Notably, the c-Kit receptor tyrosine kinase and its ligand stem cell factor were significantly elevated in TIC. The use of c-Kit siRNA or small molecule inhibitor imatinib to inhibit c-Kit expression and kinase activity, respectively, in TIC resulted in diminished cell proliferation and survival and in vivo tumorigenicity, confirming that the effect was c-Kit specific. Furthermore, we showed that while the two front-line chemotherapeutic drugs cisplatin and paclitaxel could eliminate non-TIC, it had no effect on TIC. Combining cisplatin/paclitaxel with c-Kit siRNA or imatinib prevented the growth of both tumor cell populations. These effects were found to be dependent on signaling of phosphatidylinositol 3-kinase/Akt, but not extracellular signal-regulated kinase 1/2. These results reveal an important role for c-Kit in regulation of self-renewal and proliferation of ovarian cancer cells, which could be selectively targeted for improved treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1102. doi:10.1158/1538-7445.AM2011-1102