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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells
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Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells

机译：细胞系衍生的结直肠癌干细胞的缺氧和谱系规格

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摘要

Hypoxia is an important regulator of normal and cancer stem cell (CSC) differentiation. Colorectal CSCs from SW1222, LS180, and CCK81 colorectal cancer-derived cell lines are able to differentiate into complex 3D lumen-containing structures in normoxia, whereas in hypoxia, they form undifferentiated dense colonies that have reduced expression of the enterocyte differentiation marker CDX1, lack goblet cell formation, and have increased expression of BMI1 and activated Notch 1. Hypoxia increases the clonogenicity of CSCs, which is cumulative as each round of hypoxia enriches for more CSCs. The hypoxic phenotype is reversible, because cells from hypoxic-dense colonies are able to reform differentiated structures when regrown in normoxia. We show that CDX1 is able to stimulate the generation of lumens even in hypoxia and has a negative feedback on BMI1 expression. Knockdown of CDX1 reduces lumen formation but does not affect goblet cell formation, suggesting that enterocytes and goblet cells form from different progenitor cells. Notch inhibition by dibenzazepine (DBZ) allowed CSCs to form goblet cells in both normoxia and hypoxia. Finally, we show that Hif1α, but not CA9, is an important mediator of the effects of hypoxia on the clonogenicity and differentiation of CSCs. In summary, hypoxia maintains the stem-like phenotype of colorectal cell line-derived CSCs and prevents differentiation of enterocytes and goblet cells by regulating CDX1 and Notch1, suggesting that this regulation is an important component of how hypoxia controls the switch between sternness and differentiation in CSCs.
机译：缺氧是正常和癌症干细胞（CSC）分化的重要调节剂。来自SW1222，LS180和CCK81结直肠癌的细胞系的结直肠CSC在常氧状态下能够分化成复杂的含3D内腔结构，而在低氧状态下，它们会形成未分化的密集菌落，从而降低肠上皮细胞分化标记CDX1的表达，缺乏杯状细胞形成，并增加了BMI1的表达并激活了Notch1。缺氧增加CSC的克隆形成性，随着每一轮缺氧使更多CSC富集，累积性逐渐增强。低氧表型是可逆的，因为低氧致密菌落的细胞在常氧条件下再生时能够重塑分化的结构。我们显示，CDX1即使在低氧条件下也能够刺激管腔的生成，并且对BMI1表达具有负反馈。击倒CDX1可减少管腔形成，但不影响杯状细胞的形成，表明肠上皮细胞和杯状细胞是由不同的祖细胞形成的。地苯二氮卓（DBZ）抑制Notch可使CSC在常氧和低氧状态下形成杯状细胞。最后，我们证明了Hif1α，而不是CA9，是缺氧对CSCs克隆形成和分化影响的重要介体。总之，缺氧通过调节CDX1和Notch1来维持大肠细胞系CSC的干样表型，并防止肠细胞和杯状细胞分化，这表明该调节是缺氧如何控制结直肠干细胞分化的重要组成部分。 CSC。

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    Trevor M. Yeung; Shaan C. Gandhi; Walter F. Bodmer;

  • 作者单位

    Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom;

    Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom;

    Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom Department of Hematology, Stanford University School of Medicine, Stanford, CA 94305;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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