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摘要 : 针对脑转移的新型治疗方法的研究工作一直受阻于机制认识的缺乏。

 针对脑转移的新型治疗方法的研究工作一直受阻于机制认识的缺乏。本文作者报告说,入侵性乳腺癌细胞和肺癌细胞会进入正常情况下起保护作用的大脑星形胶质细胞网络来支持转移。通过建立间隙连接,肿瘤细胞会在星形胶质细胞中触发先天免疫反应信号传导的激活,这些星形胶质细胞然后会分泌支持转移生长和化疗抗药性的因子。间隙连接抑制剂 “meclofenamate” 和 “tonabersat” 干扰这一 “旁分泌环” (paracrine loop),抑制实验性脑转移瘤的生长,这说明它们在临床上可能是有效的。


Carcinoma–astrocyte gap junctions promote brain metastasis by cGAMP transfer


Brain metastasis represents a substantial source of morbidity and mortality in various cancers, and is characterized by high resistance to chemotherapy. Here we define the role of the most abundant cell type in the brain, the astrocyte, in promoting brain metastasis. We show that human and mouse breast and lung cancer cells express protocadherin 7 (PCDH7), which promotes the assembly of carcinoma–astrocyte gap junctions composed of connexin 43 (Cx43). once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells use these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines such as interferon-α (IFNα) and tumour necrosis factor (TNF). As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, thereby supporting tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions meclofenamate and tonabersat break this paracrine loop, and we provide proof-of-principle that these drugs could be used to treat established brain metastasis.

来源: Nature 浏览次数:0


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