Expansion of hepatic tumor progenito cell population in PTEN deficient mice requires liver injury and is reversed by deletion of Akt2

We found that hepatic injury induced by PTEN loss establishes a selection pressure for tumorinitiating cells (TICs) to proliferate and form mixed lineage tumors. The Pten null mice demonstrate escalating levels of hepatic injury prior to proliferation of hepatic progenitors. Attenuation of hepatic injury by deleting Akt2 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. Pten/Akt2 double mutant (PtenloxP/loxP; Akt2-/-; Alb-Cre+) (Dm) were generated by crossing the PtenloxP/loxP; Alb-Cre+ (Pm) with the Akt2-/- mice [19]. Control animals are PtenloxP/loxP; Albumin (Alb)-Cre-.我们发现，PTEN缺失诱导的肝损伤会对肿瘤起始细胞（Tumor-Initiating Cells, TICs）施加选择压力，使其增殖并形成混合谱系肿瘤。Pten基因敲除小鼠在肝祖细胞增殖之前，会出现进行性加重的肝损伤。通过敲除Akt2减轻肝损伤，可降低祖细胞增殖并延缓肿瘤发生。使用3,5-二乙氧羰基-1,4-二氢可力丁（3,5-dietoxycarbonyl-1,4 dihydrocollidine, DDC）处理双突变小鼠的实验表明，AKT2缺失的主要作用是减轻肝损伤，而非抑制损伤应答过程中的祖细胞增殖。Pten/Akt2双突变（PtenloxP/loxP; Akt2-/-; Alb-Cre+）（简称Dm）小鼠通过将PtenloxP/loxP; Alb-Cre+小鼠（简称Pm）与Akt2-/-小鼠杂交获得[19]。对照组动物为PtenloxP/loxP; 白蛋白（Albumin, Alb）-Cre-小鼠。