Tumor-induced disruption of the blood-brain barrier promotes host death.
Tumor-induced disruption of the blood-brain barrier promotes host death.
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DOI：
10.1016/j.devcel.2021.08.010
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发表时间：
2021-10-11
影响因子：
11.8
通讯作者：
Bilder D
中科院分区：
文献类型：
--
作者：
Kim J;Chuang HC;Wolf NK;Nicolai CJ;Raulet DH;Saijo K;Bilder D
癌症患者往往死于与肿瘤有一定距离的症状。这些系统性生理扰动的机制，称为副肿瘤综合征，可能受益于对非哺乳动物系统的研究。使用非转移性果蝇成年模型，我们发现恶性肿瘤产生的细胞因子驱动宿主广泛激活JAK-STAT信号并导致过早死亡。STAT活性在血脑屏障（BBB）细胞中特别高，在那里它诱导异常的血脑屏障通透性。值得注意的是，抑制血脑屏障中的STAT不仅可以恢复屏障功能，还可以延长荷瘤宿主的寿命。我们发现血脑屏障损伤在其他病理条件下引起炎症信号升高，包括肥胖和感染，其中血脑屏障通透性也调节宿主生存。在小鼠肿瘤模型中进一步观察到il -6依赖性血脑屏障功能障碍，它再次促进宿主发病率。因此，血脑屏障改变是一种保守的致死性肿瘤-宿主相互作用，也是其他生理疾病的基础。Kim等人利用果蝇癌症模型揭示了肿瘤的全身性效应，其中炎症信号可穿透血脑屏障。防止屏障的渗透性可以使果蝇在相同的肿瘤负荷下活得更长，这些数据的关键方面在小鼠肿瘤模型中得到了概括。
Cancer patients often die from symptoms that manifest at a distance from any tumor. Mechanisms underlying these systemic physiological perturbations, called paraneoplastic syndromes, may benefit from investigation in non-mammalian systems. Using a non-metastatic Drosophila adult model, we find that malignant tumor-produced cytokines drive widespread host activation of JAK-STAT signaling and cause premature lethality. STAT activity is particularly high in cells of the blood-brain barrier (BBB), where it induces aberrant BBB permeability. Remarkably, inhibiting STAT in the BBB not only rescues barrier function but also extends the lifespan of tumor-bearing hosts. We identify BBB damage in other pathological conditions that cause elevated inflammatory signaling, including obesity and infection, where BBB permeability also regulates host survival. IL-6-dependent BBB dysfunction is further seen in a mouse tumor model, and it again promotes host morbidity. Therefore, BBB alterations constitute a conserved lethal tumor-host interaction that also underlies other physiological morbidities. Kim et al. use a fly cancer model to uncover a systemic effect of tumors, in which inflammatory signaling permeabilizes the blood-brain barrier. Preventing barrier permeability allows flies to live longer with the same tumor burden, and key aspects of these data are recapitulated in a mouse tumor model.
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影响因子：
7.7
作者：
Bunker BD;Nellimoottil TT;Boileau RM;Classen AK;Bilder D
通讯作者：
Bilder D
影响因子：
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8.8
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7.3
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通讯作者：
Bach EA
影响因子：
3.5
作者：
Mai SHC;Sharma N;Kwong AC;Dwivedi DJ;Khan M;Grin PM;Fox-Robichaud AE;Liaw PC
通讯作者：
Liaw PC