Department of Pain Management, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233, China.
Department of Clinical Laboratory, Liaocheng People's Hospital, Liaocheng 252000, China.
Acta Biochim Biophys Sin (Shanghai). 2020 Dec 29;52(12):1299-1305. doi: 10.1093/abbs/gmaa127.
Brain metastasis affects approximately 20%-30% of patients with triple-negative breast cancers (TNBCs). Even small metastatic lesions in the brain can trigger severe neurological impairments and result in extremely short survival time. Recently, active astrocytes were reported to be associated with brain metastases. However, how activated astrocytes regulate the behaviors of disseminated breast cancer cells in the brain remains unknown. In this study, human primary astrocytes were stimulated with IL-1β to form active astrocytes to study the cross-talk between stromal cells (astrocytes) and TNBC cells in brain metastases. Our results showed that active astrocytes significantly increase the malignancy of TNBC cells and prevent them from undergoing apoptosis caused by doxorubicin. We also found that the high level of IL-6 secreted by activated astrocytes was responsible for the drug resistance of breast cancer, which could be abolished by treatment of astrocytes with tamoxifen (TAM). The blockage of active astrocyte-derived IL-6 by a neutralizing antibody resulted in the attenuation of drug resistance, consequently enhancing the sensitivity of breast cancer cells to doxorubicin. Furthermore, the possible involved TAM-modulated drug resistance mechanism may be associated with a decrease in IL-6 expression in astrocytes and the downregulation of MAPK and JAK2/STAT3 signaling in cancer cells. Our data suggested that TAMs might reduce drug resistance through the IL-6/JAK2/STAT3 signaling pathway, providing a possible therapy to treat brain metastasis in TNBCs, as estrogen receptor inhibitors (TAMs, etc.) can cross the blood-brain barrier.
脑转移影响大约 20%-30%的三阴性乳腺癌（TNBC）患者。即使是大脑中的微小转移性病变也会引发严重的神经损伤，并导致极短的生存时间。最近，有研究报道活跃的星形胶质细胞与脑转移有关。然而，激活的星形胶质细胞如何调节播散性乳腺癌细胞在大脑中的行为尚不清楚。在这项研究中，用白细胞介素-1β（IL-1β）刺激人原代星形胶质细胞形成活跃的星形胶质细胞，以研究基质细胞（星形胶质细胞）与脑转移中的 TNBC 细胞之间的串扰。我们的结果表明，活跃的星形胶质细胞显著增加了 TNBC 细胞的恶性程度，并阻止它们因阿霉素而发生凋亡。我们还发现，激活的星形胶质细胞分泌的高水平白细胞介素-6（IL-6）是乳腺癌耐药的原因，用他莫昔芬（TAM）处理星形胶质细胞可以消除这种耐药性。用中和抗体阻断活性星形胶质细胞衍生的 IL-6 导致耐药性减弱，从而增强了乳腺癌细胞对阿霉素的敏感性。此外，TAM 调节的可能耐药机制可能与星形胶质细胞中 IL-6 表达的减少以及癌细胞中 MAPK 和 JAK2/STAT3 信号通路的下调有关。我们的数据表明，TAMs 可能通过 IL-6/JAK2/STAT3 信号通路降低耐药性，为治疗 TNBC 脑转移提供了一种可能的治疗方法，因为雌激素受体抑制剂（如 TAMs 等）可以穿过血脑屏障。
