Lunardi Andrea, Webster Kaitlyn A, Papa Antonella, Padmani Bhavik, Clohessy John G, Bronson Roderick T, Pandolfi Pier Paolo
Oncotarget. 2014 Feb 28;5(4):894-900. doi: 10.18632/oncotarget.1808.
The PI3K/AKT pathway governs a plethora of cellular processes, including cell growth, proliferation, and metabolism, in response to growth factors and cytokines. By acting as a unique lipid phosphatase converting phosphatidylinositol-3,4,5,- trisphosphate (PIP3) to phosphatidylinositol-4,5,-bisphosphate (PIP2), phosphatase and tensin homolog (PTEN) acts as the major cellular suppressor of PI3K signaling and AKT activation. Recently, PI3K mutations and loss/mutation of PTEN have been characterized in human gallbladder tumors; whether aberrant PTEN/PI3K pathway plays a causal role in gallbladder carcinogenesis, however, remains unknown. Herein we show that in mice, deregulation of PI3K/AKT signaling is sufficient to transform gallbladder epithelial cells and trigger fully penetrant, highly proliferative gallbladder tumors characterized by high levels of phospho-AKT. Histopathologically, these mouse tumors faithfully resemble human adenomatous gallbladder lesions. The identification of PI3K pathway deregulation as both an early event in the neoplastic transformation of the gallbladder epithelium and a main mechanism of tumor growth in Pten heterozygous and Pten mutant mouse models provides a new framework for studying in vivo the efficacy of target therapies directed against the PI3K pathway, as advanced metastatic tumors are often addicted to "trunkular" mutations.
PI3K/AKT信号通路调控着众多细胞过程，包括细胞生长、增殖和代谢，以响应生长因子和细胞因子。磷酸酶和张力蛋白同源物（PTEN）作为一种独特的脂质磷酸酶，可将磷脂酰肌醇-3,4,5-三磷酸（PIP3）转化为磷脂酰肌醇-4,5-二磷酸（PIP2），它是PI3K信号传导和AKT激活的主要细胞抑制因子。最近，在人类胆囊肿瘤中已发现PI3K突变以及PTEN的缺失/突变；然而，异常的PTEN/PI3K信号通路在胆囊癌发生过程中是否起因果作用仍不清楚。在此我们表明，在小鼠中，PI3K/AKT信号传导失调足以使胆囊上皮细胞发生转化，并引发完全显性、高度增殖的胆囊肿瘤，其特征为磷酸化AKT水平升高。从组织病理学角度来看，这些小鼠肿瘤与人类腺瘤性胆囊病变极为相似。在Pten杂合和Pten突变小鼠模型中，PI3K信号通路失调被确定为胆囊上皮肿瘤转化的早期事件以及肿瘤生长的主要机制，这为在体内研究针对PI3K信号通路的靶向治疗疗效提供了一个新的框架，因为晚期转移性肿瘤通常依赖于“主干”突变。
