Metastatic Breast Cancer Cells Enter Into Dormant State and Express Cancer Stem Cells Phenotype Under Chronic Hypoxia
Metastatic Breast Cancer Cells Enter Into Dormant State and Express Cancer Stem Cells Phenotype Under Chronic Hypoxia
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DOI：
10.1002/jcb.25972
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发表时间：
2017-10-01
影响因子：
4
通讯作者：
Mariotto, Sofia
中科院分区：
文献类型：
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作者：
de Prati, Alessandra Carcereri;Butturini, Elena;Mariotto, Sofia
肿瘤休眠是肿瘤进展中一个知之甚少的阶段，其特征是有丝分裂周期停滞在G 0/G1期和低代谢。细胞在静止状态下存活，并等待合适的环境条件再次开始增殖，从而引起转移。尽管它们在癌症发展和转移中起着关键作用，但由于忠实再现肿瘤休眠的体外模型的缺乏，关于它们的生物学和起源的知识仍然非常有限。利用至少三个循环的1%O-2缺氧和复氧，我们建立并表征了耐缺氧的人乳腺癌细胞系chMDA-MB-231，其能够在1%O-2条件下稳定存活，进入以G 0/G1期停滞和低代谢为特征的休眠状态。这种休眠状态是可逆的，因为一旦在常氧下被替换，细胞在2周内恢复增殖速率。我们发现，慢性缺氧诱导自噬，这可能是chMDA-MB-231细胞的生存机制。此外，本工作中的数据表明，循环缺氧/复氧应激选择了呈现癌干细胞样表型的MDA-MB-231群体，其特征在于CD 24（-）/CD 44（+）/ESA（+）表达和球状体形成能力。我们相信，我们的研究提出了一种有前途的方法来选择休眠的乳腺癌细胞干细胞样表型使用缺氧/复氧方案，可能代表了一个领域的肿瘤治疗的发展具有深远的影响。(C)2017 Wiley Periodicals，Inc.
Tumor dormancy is a poorly understood stage in cancer progression characterized by mitotic cycle arrest in G0/G1 phase and low metabolism. The cells survive in a quiescent state and wait for appropriate environmental conditions to begin proliferation again giving rise to metastasis. Despite their key role in cancer development and metastasis, the knowledge about their biology and origin is still very limited due to the poorness of established in vitro models that faithfully recapitulated tumor dormancy. Using at least three cycles of 1% O-2 hypoxia and reoxygenation, we establish and characterize the hypoxia-resistant human breast cancer cell line chMDA-MB-231 that can stably survive under 1% O-2 condition by entering into dormant state characterized by arrest in G0/G1 phase and low metabolism. This dormant state is reversible since once replaced in normoxia the cells recover the proliferation rate in 2 weeks. We show that chronic hypoxia induces autophagy that may be the survival mechanism of chMDA-MB-231 cells. Furthermore, the data in this work demonstrate that cycling hypoxic/reoxygenation stress selects MDA-MB-231 population that presents the cancer stem-like phenotype characterized by CD24(-)/CD44(+)/ESA(+) expression and spheroid forming capacity. We believe that our study presents a promising approach to select dormant breast cancer cells with stem-like phenotype using the hypoxia/reoxygenation regimen that may represent an area with profound implications for therapeutic developments in oncology. (C) 2017 Wiley Periodicals, Inc.