Phenotypic heterogeneity of disseminated tumour cells is preset by primary tumour hypoxic microenvironments.
Phenotypic heterogeneity of disseminated tumour cells is preset by primary tumour hypoxic microenvironments.
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DOI：
10.1038/ncb3465
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发表时间：
2017-02
影响因子：
21.3
通讯作者：
Aguirre-Ghiso JA
中科院分区：
文献类型：
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作者：
Fluegen G;Avivar-Valderas A;Wang Y;Padgen MR;Williams JK;Nobre AR;Calvo V;Cheung JF;Bravo-Cordero JJ;Entenberg D;Castracane J;Verkhusha V;Keely PJ;Condeelis J;Aguirre-Ghiso JA
缺氧是实体肿瘤预后不良的微环境标志，但目前尚不清楚它如何影响靶器官中播散性肿瘤细胞（dtc）的命运。在这里，我们报道了缺氧的HNSCC和乳腺原发性肿瘤微环境显示出关键休眠（NR2F1, DEC2, p27）和缺氧（GLUT1, HIF1α）基因的上调。对PDX和转基因小鼠的孤立dtc的分析显示，缺氧后dtc多为NR2F1hi/DEC2hi/p27hi/TGFβ2hi，处于休眠状态。缺氧后休眠dtc中p27的诱导需要NR2F1和HIF1α，但这些dtc不表达GLUT1hi。缺氧后的dtc逃避化疗，与ER -乳腺癌细胞不同，缺氧后的ER+乳腺癌细胞更容易进入依赖nr2f1的休眠状态。我们提出原发性肿瘤缺氧微环境导致休眠dtc亚群逃避治疗。这些缺氧后休眠的dtc可能是疾病复发和与缺氧相关的不良预后的来源。
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 NR2F1hi/DEC2hi/p27hi/TGFβ2hi and dormant. NR2F1 and HIF1α were required for p27 induction in post-hypoxic dormant DTCs, but these DTCs did not display GLUT1hi 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.