Fluegen Georg, Avivar-Valderas Alvaro, Wang Yarong, Padgen Michael R, Williams James K, Nobre Ana Rita, Calvo Veronica, Cheung Julie F, Bravo-Cordero Jose Javier, Entenberg David, Castracane James, Verkhusha Vladislav, Keely Patricia J, Condeelis John, Aguirre-Ghiso Julio A
Department of Medicine and Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA.
Department of General, Visceral and Pediatric Surgery, Medical Faculty, University Hospital of the Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany.
Nat Cell Biol. 2017 Feb;19(2):120-132. doi: 10.1038/ncb3465. Epub 2017 Jan 23.
Hypoxia is a poor-prognosis microenvironmental hallmark of solid tumours, but it is unclear how it influences the fate of disseminated tumour cells (DTCs) in target organs. Here we report that hypoxic HNSCC and breast primary tumour microenvironments displayed upregulation of key dormancy (NR2F1, DEC2, p27) and hypoxia (GLUT1, HIF1α) genes. Analysis of solitary DTCs in PDX and transgenic mice revealed that post-hypoxic DTCs were frequently NR2F1/DEC2/p27/TGFβ2 and dormant. NR2F1 and HIF1α were required for p27 induction in post-hypoxic dormant DTCs, but these DTCs did not display GLUT1 expression. Post-hypoxic DTCs evaded chemotherapy and, unlike ER breast cancer cells, post-hypoxic ER breast cancer cells were more prone to enter NR2F1-dependent dormancy. We propose that primary tumour hypoxic microenvironments give rise to a subpopulation of dormant DTCs that evade therapy. These post-hypoxic dormant DTCs may be the source of disease relapse and poor prognosis associated with hypoxia.
缺氧是实体瘤预后不良的微环境特征，但尚不清楚它如何影响靶器官中播散肿瘤细胞（DTC）的命运。在此，我们报告缺氧的头颈部鳞状细胞癌和乳腺原发性肿瘤微环境显示关键休眠（NR2F1、DEC2、p27）和缺氧（GLUT1、HIF1α）基因上调。对人源肿瘤异种移植模型（PDX）和转基因小鼠中单个DTC的分析表明，缺氧后DTC通常为NR2F1/DEC2/p27/TGFβ2阳性且处于休眠状态。NR2F1和HIF1α是缺氧后休眠DTC中诱导p27所必需的，但这些DTC不表达GLUT1。缺氧后DTC逃避化疗，并且与雌激素受体（ER）阳性乳腺癌细胞不同，缺氧后ER阳性乳腺癌细胞更易于进入依赖NR2F1的休眠状态。我们提出原发性肿瘤缺氧微环境会产生逃避治疗的休眠DTC亚群。这些缺氧后休眠的DTC可能是与缺氧相关的疾病复发和预后不良的根源。
