|
针对脑转移的新型治疗方法研究工作一直受阻于机制认识缺乏。 2016年5月26日，英国《自然》正式发表美国纽约纪念斯隆·凯特琳癌症中心（纽约肿瘤医院）的研究报告，发现侵袭性乳腺癌细胞可进入正常情况下起保护作用的大脑星形胶质细胞网络导致脑转移。通过建立间隙连接，肿瘤细胞可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分泌支持转移生长和化疗耐药性的因子。间隙连接抑制剂——甲氯灭酸盐（抗骨关节炎和类风湿性关节炎药） 和托那博沙（抗惊厥药）干扰这一旁分泌环，抑制实验性脑转移瘤的生长，这说明其在临床上可能有效。
Nature. 2016 May 26;533(7604):493-8. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Chen Q, Boire A, Jin X, Valiente M, Er EE, Lopez-Soto A, Jacob LS, Patwa R, Shah H, Xu K, Cross JR, Massagué J. Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. 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. PMID: 27225120 DOI: 10.1038/nature18268 |
|
|
