Angiopoietin-2 promotes ER+ breast cancer cell survival in bone marrow niche.
Angiopoietin-2 promotes ER+ breast cancer cell survival in bone marrow niche.
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DOI：
10.1530/erc-16-0086
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发表时间：
2016-08
影响因子：
3.9
通讯作者：
Cho NH
中科院分区：
文献类型：
--
作者：
Han HH;Kim BG;Lee JH;Kang S;Kim JE;Cho NH
在雌激素受体阳性（ER+）乳腺癌中，人们认识到在长期休眠后可能会发生转移。骨髓（BM）血管生态位是休眠肿瘤细胞最有可能驻留的地方。迄今为止，尚不完全清楚为什么休眠的肿瘤细胞会增殖并最终产生肿瘤。我们假设治疗性或更年期相关的雌激素消耗可能是 BM 中休眠的 ER+ 肿瘤细胞苏醒的开关。我们利用现有的可模拟 ER+ 肿瘤细胞休眠的 BM 内皮微环境实验模型来检验我们的假设。结果，雌激素消耗反而促进了 BM 内皮微环境中 ER+ 肿瘤细胞的增殖，并且它们的分子表型从休眠转变为唤醒。雌激素耗尽后，BM 生态位细胞产生血管生成素-2 (ANGPT2)，它通过干扰 ANGPT1/Tie2 信号传导破坏生态位内皮的稳定，并通过细胞表面整合素 &1 促进雌激素缺乏下 ER+ 肿瘤细胞的存活。 ANGPT2 的敲低完全否定了微环境中 ER+ 肿瘤细胞的唤醒。此外，ER+肿瘤人类样本中的ANGPT2表达仅在接受辅助雌激素消耗治疗的患者中与远处转移风险增加相关，而在未接受辅助治疗的患者中则不然。总之，我们证明，雌激素耗竭后激活的 ANGPT2 信号传导矛盾地触发 ER+ 肿瘤细胞从其 BM 生态位的休眠状态中唤醒，部分通过内皮 Tie2 受体间接，部分直接通过肿瘤细胞表面整合素 &1。
In estrogen receptor-positive (ER+) breast cancer, it is recognized that metastases may develop after a long period of dormancy. Bone marrow (BM) vascular niche is where the dormant tumor cells are most likely to reside. So far, it is not fully understood why the dormant tumor cells become proliferative and eventually generate tumor. We hypothesized that therapeutic or menopause-related estrogen depletion may be the switch behind dormant ER+ tumor cell awakening in BM. We utilized an existing experimental model of BM endothelial niche that can simulate ER+ tumor cell dormancy to test our hypothesis. In results, estrogen depletion paradoxically promoted ER+ tumor cell proliferation in the BM endothelial niche, and their molecular phenotype shifted from dormant to awaken. Following estrogen depletion, the BM niche cells produced angiopoietin-2 (ANGPT2), which destabilized niche endothelium by interfering ANGPT1/Tie2 signaling, and promoted ER+ tumor cell survival under estrogen deficiency via cell surface integrin &1. Knockdown of ANGPT2 completely negated ER+ tumor cell awakening in the niche. Furthermore, ANGPT2 expression in ER+ tumor human samples was associated with increased risk of distant metastasis only in those who underwent adjuvant estrogen depletion therapy, not in those who did not undergo adjuvant therapy. In conclusion, we demonstrate that ANGPT2 signaling activated after estrogen depletion paradoxically triggers ER+ tumor cell awakening from dormancy in their BM niche, partly indirectly via endothelial Tie2 receptor and partly directly via tumor cell surface integrin &1.