CD95 is a key mediator of invasion and accelerated outgrowth of mouse colorectal liver metastases following radiofrequency ablation
CD95 is a key mediator of invasion and accelerated outgrowth of mouse colorectal liver metastases following radiofrequency ablation
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DOI：
10.1016/j.jhep.2010.04.040
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发表时间：
2010-12-01
影响因子：
25.7
通讯作者：
Kranenburg, Onno
中科院分区：
文献类型：
--
作者：
Nijkamp, Maarten W.;Hoogwater, Frederik J. H.;Kranenburg, Onno
背景与应用最近我们发现射频消融（RFA）产生的病灶周围缺氧过渡区的微转移显示出强烈的加速生长CD95最为人所知的是其诱导凋亡的能力，但也可以促进耐凋亡肿瘤细胞的肿瘤发生。因此我们测试了CD95信号传导是否在RFA后结直肠肝转移的加速生长中起作用。通过共聚焦显微镜在三维表达EGFP的C26肿瘤细胞培养物中评估诱导的侵袭，通过免疫荧光检测CD95定位，通过后处理分析RFA后肝转移瘤的侵袭和生长。通过使用抗体MFL 4进行CD95 L的中和，通过慢病毒RNA干扰抑制CD95。结果射频消融后低氧移行区微转移瘤表现为高度侵袭性表型，CD95和CD95L表达增加。体外诱导的肿瘤细胞侵袭增加了CD95和CD95L的表达，并诱导CD95易位到侵袭前沿。结论低氧可激活结直肠癌细胞表面CD95自分泌，从而促进肿瘤局部浸润，加速肿瘤在低氧过渡区的生长。需要进行临床研究，以评估CD95 L中和单独或联合化疗在限制RFA后肝转移侵袭性复发中的作用（C）2010年欧洲肝脏研究协会Elsevier B V出版版权所有
Background & Alms Recently we have shown that miciometastases in the hypoxic transition zone surrounding lesions generated by radiofrequency ablation (RFA) display strongly accelerated outgrowth CD95 is best known for its ability to induce apoptosis but can also promote tumorigenesis in apoptosis-resistant tumor cells Therefore we tested whether CD95 signaling plays a role in accelerated outgrowth of colorectal liver metastases following RFAMethods Hypoxia-induced invasion was assessed in three-dimensional EGFP-expressing C26 tumor cell cultures by confocal microscopy CD95 localization was tested by immunofluorescence Invasion and outgrowth of liver metastases following RFA were analyzed by post-mortem confocal microscopy and by morphometric assessment of tumor load Neutralization of CD95L was performed by using antibody MFL4 CD95 was suppressed by lentiviral RNA Interference The role of host CD95L was assessed using gld miceResults Micro-metastases in the hypoxic transition zone following RFA displayed a highly invasive phenotype and Increased expression of CD95 and CD95L Hypoxia-induced tumor cell invasion in vitro increased the expression of CD95 and CD95L and induced translocation of CD95 to the invasive front In vitro invasion metastasis invasion and accelerated tumor growth in the transition zone were strongly suppressed by neutralizing CD95L or by suppressing tumor cell CD95 In contrast metastasis invasion and outgrowth were unaffected in gld miceConclusions Hypoxia causes autocrine activation of CD95 on colorectal tumor cells thereby promoting local invasion and accelerated metastasis outgrowth in the hypoxic transition zone following RFA Further pre-clinical work is needed to assess the role of CD95L neutralization either alone or in combination with chemotherapy in limiting aggressive recurrence of liver metastases following RFA (C) 2010 European Association for the Study of the Liver Published by Elsevier B V All rights reserved