Abstract 4260: Activation of cancer stem cells in hepatic Pten deficient mice requires liver injury

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-04, Vol.70 (8_Supplement), p.4260-4260
• Main Authors: Galicia, Vivian A., Kanel, Gary, He, Lina, Vendryes, Christopher, Stiles, Bangyan L.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM10-4260

Cancer stem cells have been identified in solid and aqueous tumors and are defined as “altered” stem cells with the capacity to form tumors. We used the liver specific Pten (phosphatase and tensin homologue deleted on chromosome ten) deletion murine model to investigate the role of hepatic cancer stem cells in vivo. Proliferation of hepatic progenitor cells in other rodent models has been observed as a consequence of chronic liver injury. Pten-null mice demonstrate escalating levels of hepatic injury markers from 6-12M of age. In addition, TUNEL analysis revealed that hepatocytes from mutant mice are undergoing extensive apoptosis relative to control mice. We hypothesize that hepatocyte cell death induced by lipotoxicity promotes progenitor cell proliferation to replace liver parenchyma. We show here that activation of hepatic progenitor cells (oval cells) in this model occurs progressively. In mutant mice hepatic injury is followed by elevated expression of hepatic progenitor cell markers Cytokeratin 19 (CK 19), Epithelial cell adhesion molecule (EpCAM), α-fetoprotein (AFP) as well as activation of the Wnt/β-Catenin signaling pathway. Furthermore, we report that liver specific Pten-null mice develop both cholangiocellular carcinoma (CC) and hepatocellular carcinoma (HCC) by 12-15 months of age. Collectively these results suggest that liver tumors in this model arise from hepatic progenitor cells. Our studies also demonstrate that when hepatic injury is attenuated tumor onset is significantly delayed, highlighting the relevance of hepatic injury to progenitor cell induced carcinogenesis. In addition, we show that reactive oxygen species (ROS) is the likely molecular mediator for hepatocyte cell death. This study presents in vivo evidence for the contribution of hepatic injury to progenitor cell mediated liver tumorigenesis. 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 4260.