Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
Cell Rep. 2021 Feb 9;34(6):108726. doi: 10.1016/j.celrep.2021.108726.
Tumor and stromal interactions consist of reciprocal signaling through cytokines, growth factors, direct cell-cell interactions, and extracellular vesicles (EVs). Small EVs (≤200 nm) have been considered critical messengers of cellular communication during tumor development. Here, we demonstrate that gain-of-function (GOF) p53 protein can be packaged into small EVs and transferred to fibroblasts. GOF p53 protein is selectively bound by heat shock protein 90 (HSP90), a chaperone protein, and packaged into small EVs. Inhibition of HSP90 activity blocks packaging of GOF, but not wild-type, p53 in small EVs. GOF p53-containing small EVs result in their conversion to cancer-associated fibroblasts. In vivo studies reveal that GOF p53-containing small EVs can enhance tumor growth and promote fibroblast transformation into a cancer-associated phenotype. These findings provide a better understanding of the complex interactions between cancer and stromal cells and may have therapeutic implications.
肿瘤与基质的相互作用包括通过细胞因子、生长因子、直接细胞-细胞相互作用和细胞外囊泡（EVs）进行的相互信号传递。小细胞外囊泡（≤200nm）被认为是肿瘤发展过程中细胞通讯的关键信使。在这里，我们证明了功能获得性（GOF）p53 蛋白可以被包装到小细胞外囊泡中并转移到成纤维细胞中。GOF p53 蛋白被热休克蛋白 90（HSP90），一种伴侣蛋白，选择性结合并包装到小细胞外囊泡中。抑制 HSP90 活性可阻止 GOF 而不是野生型 p53 包装到小细胞外囊泡中。含有 GOF p53 的小细胞外囊泡导致其转化为癌相关成纤维细胞。体内研究表明，含有 GOF p53 的小细胞外囊泡可以增强肿瘤生长并促进成纤维细胞转化为癌相关表型。这些发现提供了对癌症与基质细胞之间复杂相互作用的更好理解，并可能具有治疗意义。
