UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street, London WC1E 6DD, U.K.
Biochem Soc Trans. 2020 Feb 28;48(1):301-315. doi: 10.1042/BST20190778.
The PI3K/AKT pathway is a key target in oncology where most efforts are focussed on phenotypes such as cell proliferation and survival. Comparatively, little attention has been paid to PI3K in stemness regulation, despite the emerging link between acquisition of stem cell-like features and therapeutic failure in cancer. The aim of this review is to summarise current known and unknowns of PI3K-dependent stemness regulation, by integrating knowledge from the fields of developmental, signalling and cancer biology. Particular attention is given to the role of the PI3K pathway in pluripotent stem cells (PSCs) and the emerging parallels to dedifferentiated cancer cells with stem cell-like features. Compelling evidence suggests that PI3K/AKT signalling forms part of a 'core molecular stemness programme' in both mouse and human PSCs. In cancer, the oncogenic PIK3CAH1047R variant causes constitutive activation of the PI3K pathway and has recently been linked to increased stemness in a dose-dependent manner, similar to observations in mouse PSCs with heterozygous versus homozygous Pten loss. There is also evidence that the stemness phenotype may become 'locked' and thus independent of the original PI3K activation, posing limitations for the success of PI3K monotherapy in cancer. Ongoing therapeutic developments for PI3K-associated cancers may therefore benefit from a better understanding of the pathway's two-layered and highly context-dependent regulation of cell growth versus stemness.
PI3K/AKT 通路是肿瘤学中的一个关键靶点，大多数研究都集中在细胞增殖和存活等表型上。相比之下，尽管在癌症中获得类似干细胞的特征与治疗失败之间存在关联，但人们对干细胞调节中的 PI3K 关注甚少。本综述的目的是通过整合发育生物学、信号转导和癌症生物学领域的知识，总结目前已知和未知的 PI3K 依赖性干细胞调节。特别关注 PI3K 通路在多能干细胞（PSCs）中的作用以及与具有干细胞样特征的去分化癌细胞之间新兴的相似性。令人信服的证据表明，PI3K/AKT 信号转导构成了小鼠和人类 PSCs 中“核心分子干细胞程序”的一部分。在癌症中，致癌的 PIK3CAH1047R 变体导致 PI3K 通路的组成性激活，并且最近以剂量依赖性方式与干细胞增加有关，类似于杂合性与纯合性 Pten 缺失的小鼠 PSCs 的观察结果。也有证据表明，干细胞表型可能变得“锁定”，因此与原始 PI3K 激活无关，这对癌症中 PI3K 单药治疗的成功构成限制。因此，针对与 PI3K 相关的癌症的治疗进展可能会受益于更好地理解该通路在细胞生长与干细胞之间的双层和高度依赖上下文的调节。
