Hypoxia-induced secretion stimulates breast cancer stem cell regulatory signalling pathways
Hypoxia-induced secretion stimulates breast cancer stem cell regulatory signalling pathways
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DOI：
10.1002/1878-0261.12500
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发表时间：
2019-08-01
影响因子：
6.6
通讯作者：
Landberg, Goran
中科院分区：
文献类型：
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作者：
Jacobsson, Hanna;Harrison, Hannah;Landberg, Goran
众所周知，肿瘤细胞依赖于与肿瘤微环境的通信。以前，它已被证明，缺氧（HX）诱导显着的，不同的和直接的影响对癌症干细胞（CSC）的质量在不同的乳腺癌亚型。在这里，我们描述了HX诱导的分泌影响CSC扩散的机制。与正常生长条件相比，来自雌激素受体（ER）-α阳性缺氧乳腺癌细胞培养物的条件培养基（CM）增加了CSC的分数，如使用CSC测定和模型系统组所确定的。相比之下，来自ER α阴性缺氧细胞培养物的培养基反而减少了癌细胞的这一关键亚群。此外，如通过CM的蛋白质筛选所确定的，在ER α阳性和ER α阴性相关的缺氧反应中，JAK-STAT相关细胞因子存在显著的过度表达。JAK-STAT抑制剂和敲低实验进一步支持了这一假设，即该途径对于低氧分泌诱导的CSC激活和CSC失活作用至关重要。我们还观察到白细胞介素-6-JAK 2-STAT 3轴是ER α阴性缺氧行为的特异性中心。我们的研究结果强调了在靶向JAK-STAT或HX相关过程的治疗中考虑乳腺癌亚型的重要性，并表明HX不仅是一种局限的肿瘤生物学事件，而且还影响了广泛的常氧微环境中的关键肿瘤特性。
It is well known that tumour cells are dependent on communication with the tumour microenvironment. Previously, it has been shown that hypoxia (HX) induces pronounced, diverse and direct effects on cancer stem cell (CSC) qualities in different breast cancer subtypes. Here, we describe the mechanism by which HX-induced secretion influences the spreading of CSCs. Conditioned media (CM) from estrogen receptor (ER)-alpha-positive hypoxic breast cancer cell cultures increased the fraction of CSCs compared to normal growth conditions, as determined using sets of CSC assays and model systems. In contrast, media from ER alpha-negative hypoxic cell cultures instead decreased this key subpopulation of cancer cells. Further, there was a striking overrepresentation of JAK-STAT-associated cytokines in both the ER alpha-positive and ER alpha-negative linked hypoxic responses as determined by a protein screen of the CM. JAK-STAT inhibitors and knockdown experiments further supported the hypothesis that this pathway is critical for the CSC-activating and CSC-inactivating effects induced by hypoxic secretion. We also observed that the interleukin-6-JAK2-STAT3 axis was specifically central for the ER alpha-negative hypoxic behaviour. Our results underline the importance of considering breast cancer subtypes in treatments targeting JAK-STAT or HX-associated processes and indicate that HX is not only a confined tumour biological event, but also influences key tumour properties in widespread normoxic microenvironments.