Cancer cells produce liver metastasis via gap formation in sinusoidal endothelial cells through proinflammatory paracrine mechanisms.
Cancer cells produce liver metastasis via gap formation in sinusoidal endothelial cells through proinflammatory paracrine mechanisms.
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DOI：
10.1126/sciadv.abo5525
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发表时间：
2022-09-30
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
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作者：
肝窦内皮细胞(LSECs)细胞内缝隙(IGAP)的形成是由窗孔破坏引起的，在病理条件下出现，但其在癌细胞向肝脏转移中的作用尚不清楚。我们阐明了肝毒素损伤和肝纤维化导致LSECs-IGAP的形成，这与脾内注射Hepa1-6细胞后肝转移灶数目的增加呈正相关。Hepa1-6细胞诱导肝内皮细胞分泌白介素23依赖的肿瘤坏死因子α，并触发肝内皮细胞α的形成，其突起向肝实质突起，向肝实质迁移。肿瘤坏死因子-α激活F-肌动蛋白解聚，诱导基质金属蛋白酶9、细胞内黏附分子1和CxCL的表达。用多西环素或MMP2/9抑制剂阻断MMP9活性可抑制LSECs-IGAP的形成，减少肝转移。总之，这项研究揭示了癌细胞通过促炎旁分泌机制诱导LSEC-IGAP的形成，并提出MMP9是阻止癌细胞向肝脏转移的有利靶点。发现了肝转移的另一种途径，表明癌细胞通过内皮细胞内间隙的形成侵袭。
Intracellular gap (iGap) formation in liver sinusoidal endothelial cells (LSECs) is caused by the destruction of fenestrae and appears under pathological conditions; nevertheless, their role in metastasis of cancer cells to the liver remained unexplored. We elucidated that hepatotoxin-damaged and fibrotic livers gave rise to LSECs-iGap formation, which was positively correlated with increased numbers of metastatic liver foci after intrasplenic injection of Hepa1-6 cells. Hepa1-6 cells induced interleukin-23–dependent tumor necrosis factor–α (TNF-α) secretion by LSECs and triggered LSECs-iGap formation, toward which their processes protruded to transmigrate into the liver parenchyma. TNF-α triggered depolymerization of F-actin and induced matrix metalloproteinase 9 (MMP9), intracellular adhesion molecule 1, and CXCL expression in LSECs. Blocking MMP9 activity by doxycycline or an MMP2/9 inhibitor eliminated LSECs-iGap formation and attenuated liver metastasis of Hepa1-6 cells. Overall, this study revealed that cancer cells induced LSEC-iGap formation via proinflammatory paracrine mechanisms and proposed MMP9 as a favorable target for blocking cancer cell metastasis to the liver. An alternative pathway for liver metastasis was discovered showing that cancer cells invade via intraendothelial gap formation.
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影响因子：
158.5
作者：
Cristofanilli, M;Budd, GT;Hayes, DF
通讯作者：
Hayes, DF
影响因子：
13.5
作者：
DeLeve, Laurie D.
通讯作者：
DeLeve, Laurie D.
DOI：
10.3791/56993
发表时间：
2018-02-12
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Cabral F;Miller CM;Kudrna KM;Hass BE;Daubendiek JG;Kellar BM;Harris EN
通讯作者：
Harris EN
影响因子：
--
作者：
GOLDBLUM, SE;DING, XD;CAMPBELLWASHINGTON, J
通讯作者：
CAMPBELLWASHINGTON, J
DOI：
10.4049/jimmunol.1000332
发表时间：
2010-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Connolly MK;Bedrosian AS;Malhotra A;Henning JR;Ibrahim J;Vera V;Cieza-Rubio NE;Hassan BU;Pachter HL;Cohen S;Frey AB;Miller G
通讯作者：
Miller G