The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors.

中文翻译：

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STAT3标记了脑转移所需的反应性星形胶质细胞的亚群。

脑微环境对转移起始细胞施加了特别强烈的选择性压力，但是成功的转移通过人们所知甚少的机制绕过了这种控制。反应性星形胶质细胞是该微环境的关键组成部分，其可限制脑转移而不浸润病变。在这里，我们描述了脑转移细胞在转移性病变周围反应性星形胶质细胞亚群中诱导和维持由信号转导子和转录激活子3（STAT3）驱动的促转移程序的共同选择。这些反应性星形胶质细胞通过对先天和后天免疫系统的调节作用使转移性细胞受益。在患者中，反应性星形胶质细胞中的活性STAT3与颅内转移癌诊断后的存活率降低相关。在反应性星形胶质细胞中阻断STAT3信号传导可减少来自不同原发肿瘤源的实验性脑转移，即使在定殖的晚期也是如此。我们还显示，抑制STAT3的安全且口服生物利用度高的治疗方法在包括脑转移在内的晚期全身性疾病患者中表现出显着的抗肿瘤作用。对这种疗法的反应在中枢神经系统中很明显，在中枢神经系统中获得了几个完整的反应。考虑到脑转移会导致大量发病和死亡，我们的研究结果确定了一种增加继发性脑肿瘤患者生存率的新疗法。我们还显示，抑制STAT3的安全且口服生物利用度高的治疗方法在包括脑转移在内的晚期全身性疾病患者中表现出显着的抗肿瘤作用。对这种疗法的反应在中枢神经系统中很明显，在中枢神经系统中获得了几个完整的反应。考虑到脑转移会导致大量发病和死亡，我们的研究结果确定了一种增加继发性脑肿瘤患者生存率的新方法。我们还表明，抑制STAT3的安全且口服生物利用度高的治疗方法可在包括脑转移在内的晚期全身性疾病患者中表现出显着的抗肿瘤作用。对这种疗法的反应在中枢神经系统中很明显，在中枢神经系统中获得了几个完整的反应。考虑到脑转移会导致大量发病和死亡，我们的研究结果确定了一种增加继发性脑肿瘤患者生存率的新疗法。