Murine Hepatocellular Carcinoma Stem Cells Express Pluripotency-associated Transcription Factors and are Sensitive to Immune Mediated Apoptosis. (101.16)

Abstract

Abstract Current evidence supports the view that cancer stem cells (CSCs) constitute the primary pathogenic component of both metastases and minimal residual disease and that elimination of CSCs is required for cure. Cell surface markers have been used to identify CSCs but fail to identify CSC in all tumors from the same tissue or in all patients. Therefore there is a need to define and test more reliable markers of CSCs. Oct-4, Sox-2 and Nanog transcription factors are key regulatory factors in maintenance of pluripotency and have been demonstrated to be robust intracellular biomarkers for tissue and cancer stem cells. A GFP-based reporter driven by a promoter responsive to Nanog or Oct-4 was used to mark pluripotent tumor cells from in vitro cultured, cancer cell lines (breast cancer- 4T1.2), and from autochthonous hepatocellular carcinoma. The molecular profile of primary Akt/β-Cat-induced murine HCC recapitulates that observed in poor prognosis Ep-CAM+/AFP+ human HCC. Ep-CAM and CD133 and Nanog and Oct-4 are independent CSC markers. Directly ex vivo, murine HCC stem cells express abundant CD1d and MHC class II in addition to TNF-R2, lymphotoxin-β receptor (LTβR) and DR5. The functional significance of CD1d, MHC class II, TNF-R2, LTβR and DR5 expression will be assessed in future studies. This study will provide valuable proof-of-principle data to the merits of CSCs as targets for curative anti-cancer therapies.