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首页> 外文期刊>Oncogene >Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche
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Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche

机译：靶向碳酸酐酶IX会耗竭缺氧环境中的乳腺癌干细胞

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The sub-population of tumor cells termed 鈥榗ancer stem cells鈥?(CSCs) possess the capability to generate tumors, undergo epithelial鈥搈esenchymal transition (EMT) and are implicated in metastasis, making treatments to specifically target CSCs an attractive therapeutic strategy. Tumor hypoxia plays a key role in regulating EMT and cancer stem cell function. Carbonic anhydrase IX (CAIX) is a hypoxia-inducible protein that regulates cellular pH to promote cancer cell survival and invasion in hypoxic microenvironments and is a biomarker of poor prognosis for breast cancer metastasis and survival. Here, we demonstrate that inhibition of CAIX expression or activity with novel small-molecule inhibitors in breast cancer cell lines, or in primary metastatic breast cancer cells, results in the inhibition of breast CSC expansion in hypoxia. We identify the mTORC1 axis as a critical pathway downstream of CAIX in the regulation of cancer stem cell function. CAIX is also required for expression of EMT markers and regulators, as well as drivers of 鈥榮temness鈥? such as Notch1 and Jagged1 in isolated CSCs. In addition, treatment of mice bearing orthotopic breast tumors with CAIX-specific small-molecule inhibitors results in significant depletion of CSCs within these tumors. Furthermore, combination treatment with paclitaxel results in enhanced tumor growth delay and eradication of lung metastases. These data demonstrate that CAIX is a critical mediator of the expansion of breast CSCs in hypoxic niches by sustaining the mesenchymal and 鈥榮temness鈥?phenotypes of these cells, making CAIX an important therapeutic target for selectively depleting breast CSCs.
机译：称为“癌干细胞”（CSCs）的肿瘤细胞亚群具有产生肿瘤，经历上皮-“间充质转化（EMT）”的能力，并且与转移有关，这使得针对特异性靶向CSC的治疗成为一种有吸引力的治疗策略。肿瘤缺氧在调节EMT和癌症干细胞功能中起关键作用。碳酸酐酶IX（CAIX）是一种低氧诱导蛋白，可调节细胞的pH值，从而促进缺氧的微环境中癌细胞的存活和侵袭，并且是乳腺癌转移和存活预后不良的生物标志。在这里，我们证明了在乳腺癌细胞系或原发性转移性乳腺癌细胞中用新型小分子抑制剂对CAIX表达或活性的抑制会导致在缺氧状态下抑制乳腺癌CSC的扩增。我们确定mTORC1轴是癌症干细胞功能调节中CAIX下游的关键途径。还需要CAIX来表达EMT标记和调节剂，以及“荣度”的驱动力。例如隔离的CSC中的Notch1和Jagged1。另外，用CAIX特异性小分子抑制剂治疗患有原位乳腺肿瘤的小鼠会导致这些肿瘤内CSC的大量消耗。此外，与紫杉醇的联合治疗导致肿瘤生长延迟增加和根除肺转移。这些数据表明，CAIX通过维持这些细胞的间充质和“荣格”表型，是缺氧部位乳腺CSCs扩张的关键介质，使CAIX成为选择性消耗乳腺CSCs的重要治疗靶标。

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