Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Cancer Center, University of Gothenburg, Sweden.
Breakthrough Breast Cancer Unit, Centre for Molecular Pathology, Institute of Cancer Sciences, Paterson Institute for Cancer Research, University of Manchester, UK.
Mol Oncol. 2019 Aug;13(8):1693-1705. doi: 10.1002/1878-0261.12500. Epub 2019 Jun 26.
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)-α-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 ERα-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 ERα-positive and ERα-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 ERα-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.
众所周知，肿瘤细胞依赖于与肿瘤微环境的交流。此前已经表明，缺氧（HX）对不同乳腺癌亚型中的癌症干细胞（CSC）特性会产生显著的、多样的和直接的影响。在这里，我们描述了 HX 诱导的分泌如何影响 CSC 扩散的机制。与正常生长条件相比，用 CSC 检测试剂盒和模型系统测定，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 的比例。相比之下，来自 ERα-阴性缺氧细胞培养物的培养基反而减少了这种关键的癌细胞亚群。此外，通过 CM 的蛋白质筛选发现，在 ERα-阳性和 ERα-阴性相关的缺氧反应中，JAK-STAT 相关细胞因子的表达显著增加。JAK-STAT 抑制剂和敲低实验进一步支持了这样的假设，即该途径对于缺氧分泌诱导的 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-JAK2-STAT3 轴对于 ERα-阴性缺氧行为特别重要。我们的研究结果强调了在针对 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 不仅是一个局限于肿瘤的生物学事件，而且还会影响广泛的常氧微环境中的关键肿瘤特性。
