Molecular pathways: intercellular PTEN and the potential of PTEN restoration therapy.
Molecular pathways: intercellular PTEN and the potential of PTEN restoration therapy.
复制标题
DOI：
10.1158/1078-0432.ccr-13-2661
复制
发表时间：
2014-11-01
期刊：
影响因子：
--
通讯作者：
Parsons RE
中科院分区：
文献类型：
--
作者：
Hopkins BD;Parsons RE
10号染色体上缺失的磷酸酶和Tensin同源物(PTEN)通过PI3K依赖和独立的机制发挥肿瘤抑制作用。PTEN活性降低不仅影响肿瘤细胞的增殖和存活，而且还影响新生肿瘤发展的微环境。由于PTEN的多方面肿瘤抑制作用，肿瘤通过选择PTEN活性丢失的克隆来进化。PTEN在肿瘤中的活性可以通过多种方式进行调节，包括直接突变、表观遗传调节以及其他可以调节或降解PTEN的蛋白质的扩增或突变。这些事件在功能上阻止了PTEN蛋白在肿瘤细胞内的作用。最近发现PTEN基因产物的旁分泌作用(外体PTEN和PTEN-L)，通过它在一个细胞中产生的PTEN基因产物能够进入受体细胞并对PTEN功能做出贡献。在临床前模型中，纯化的PTEN-L蛋白能够进入肿瘤移植瘤，下调PI3K信号转导，并导致肿瘤细胞死亡。在这里，我们回顾了PTEN作为一个多方面的肿瘤抑制因子的作用，并反思了PTEN修复治疗的潜力。
Phosphatase and Tensin homologue deleted on chromosome ten (PTEN) acts a tumor suppressor through both PI3K dependent and independent mechanisms. Reduced PTEN activity has been shown to affect not only tumor cell proliferation and survival but also impacts the micro-environmental context in which nascent tumors develop. As a result of PTEN’s multifaceted tumor suppressive roles, tumors evolve by selecting for clones in which PTEN activity is lost. PTEN activity within tumors can be modulated in numerous ways including direct mutation, epigenetic regulation, and amplification or mutation of other proteins that can regulate or degrade PTEN. These events functionally prevent PTEN protein from acting within tumor cells. Paracrine roles for PTEN gene products (exosomal PTEN, and PTEN-L) have recently been identified, through which PTEN gene products produced in one cell are able to enter recipient cells and contribute to PTEN functions. In preclinical models purified PTEN-L protein was able to enter tumor xenografts and down regulate PI3K signaling as well as cause tumor cell death. Here we review PTEN’s role as a multifaceted tumor suppressor and reflect upon the potential for PTEN restoration therapy.