PTEN deletion induced tumor initiating cells: Strategies to accelerate the disease progression of liver cancer

UnrestrictedProgenitor or tumor initiating cells (TICs) are “altered” stem cells with the capacity to form solid tumors. Tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome ten) and its downstream target Protein Kinase B (AKT2) are aberrantly expressed in liver cancers. The focus of my doctoral studies is to use liver specific Pten (Pm) and Pten/Akt2 deletion (Dm) murine models to investigate the role of hepatic TICs in vivo. Proliferation of hepatic progenitor cells in has been reported in various murine models of hepatotoxin induced liver injury. Pm mice develop liver cancer following an extensive phase of chronic lipid accumulation and demonstrate escalating levels of hepatic injury markers from 6-12M, prior to TIC proliferation. In addition, TUNEL analysis revealed that hepatocytes from Pm mice undergo extensive apoptosis relative to control mice. We hypothesize that hepatocyte cell death induced by hepatic injury presents an opportunity for TICs to proliferate and consequently form mixed lineage tumors. Based on these findings, I sought to investigate different strategies employed by TICs for liver tumor development. The first is taking advantage of an injured niche which is addressed in chapter two. Attenuation of hepatic injury by Akt2 deletion reduces progenitor cell proliferation and delays tumor development. Treatment of double mutant mice with 3,5-dietoxycarbonyl-1,4 dihydrocollidine (DDC) shows that the primary effect of AKT2 loss is attenuation of hepatic injury and not inhibition of progenitor cell proliferation in response to injury. My primary study also revealed that the Wnt/β-Catenin signaling pathway is the likely molecular mediator of cancer stem cell proliferation in our Pm model. In chapter three we explore inhibition of the Wnt/β-Catenin signaling pathway as a means to inhibit TIC proliferation. We demonstate that Wnt/β-Catenin inhibitor ICG-001 attenuates proliferation of hepatic tumor initiating cell line P0.; Lastly, we explore evasion of cell cycle regulation by cancer stem cells using hepatic LKB1/Pten deletion (DM). This study revealed that monoallelic deletion of LKB1 in Pm mice causes an earlier onset of bilineage liver cancer development. This acceleration of tumor formation is associated with disregulation of cell cycle inhibitor p21. The findings from these studies are not only relevant to liver cancer research, but to multiple organ cancer stem cell systems which may employ similar tactics for malignant transformation