Department of Hematology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; andVascular Program, Institute for Cell Engineering.
Vascular Program, Institute for Cell Engineering,McKusick-Nathans Institute of Genetic Medicine, and Departments of.
Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):E3234-42. doi: 10.1073/pnas.1410041111. Epub 2014 Jun 17.
Extracellular vesicles such as exosomes and microvesicles (MVs) are shed by cancer cells, are detected in the plasma of cancer patients, and promote cancer progression, but the molecular mechanisms regulating their production are not well understood. Intratumoral hypoxia is common in advanced breast cancers and is associated with an increased risk of metastasis and patient mortality that is mediated in part by the activation of hypoxia-inducible factors (HIFs). In this paper, we report that exposure of human breast cancer cells to hypoxia augments MV shedding that is mediated by the HIF-dependent expression of the small GTPase RAB22A, which colocalizes with budding MVs at the cell surface. Incubation of naïve breast cancer cells with MVs shed by hypoxic breast cancer cells promotes focal adhesion formation, invasion, and metastasis. In breast cancer patients, RAB22A mRNA overexpression in the primary tumor is associated with decreased overall and metastasis-free survival and, in an orthotopic mouse model, RAB22A knockdown impairs breast cancer metastasis.
细胞外囊泡（如外泌体和微泡（MVs））是由癌细胞释放的，可在癌症患者的血浆中检测到，并促进癌症的进展，但调节其产生的分子机制尚不清楚。在晚期乳腺癌中，肿瘤内缺氧很常见，并且与转移和患者死亡率增加有关，部分原因是缺氧诱导因子（HIFs）的激活。在本文中，我们报告说，人乳腺癌细胞暴露于缺氧会增加 MV 的释放，这是由 HIF 依赖性的小 GTPase RAB22A 的表达介导的，RAB22A 与细胞表面的出芽 MV 共定位。用缺氧乳腺癌细胞释放的 MV 孵育原代乳腺癌细胞可促进黏附斑形成、侵袭和转移。在乳腺癌患者中，原发性肿瘤中 RAB22A mRNA 的过表达与总生存期和无转移生存期缩短相关，在原位小鼠模型中，RAB22A 敲低可损害乳腺癌转移。
