Enhanced colorectal cancer metastases in the alcohol-injured liver
Enhanced colorectal cancer metastases in the alcohol-injured liver
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DOI：
10.1007/s10585-017-9838-x
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发表时间：
2017-02-01
影响因子：
4
通讯作者：
McVicker, Benita L.
中科院分区：
文献类型：
--
作者：
Mohr, Ashley M.;Gould, John J.;McVicker, Benita L.
转移性肝病是结直肠癌（CRC）患者死亡的主要原因。饮酒是继发性癌症的一个值得注意的危险因素，但酒精性肝病 (ALD) 在结直肠肝转移 (CRLM) 中的作用尚未确定。这项工作使用人类结直肠癌肝转移的新型临床前模型评估了酒精宿主肝脏中肿瘤细胞的定植。免疫功能低下的 Rag1 缺陷小鼠在脾内注射 LS174T 人 CRC 细胞之前，先喂食乙醇 (E) 或等热量对照 (C) 饮食 4 周。注射 LS174T 细胞后 3 或 5 周，持续给予 C/E 饮食，对 ALD 和 CRLM 进行评估。 ALD 通过血清转氨酶升高、肝脂肪变性和细胞色素 P4502E1（一种主要乙醇代谢酶）的表达来证实。酒精介导的肝功能障碍通过脱唾液酸类粘蛋白和癌胚抗原 (CEA) 的内吞作用受损来验证，它们分别是肝细胞损伤和进展性结直肠癌疾病的指标。引人注目的是，在酒精肝中，CRLM 的发生率和负担明显增强，并且在 E 喂养的小鼠中观察到的转移更早且更严重。此外，在肝细胞因子（TNF-α、IL-1β、IL-6、IL-10）和其他与 CRC 细胞定植有关的因子（包括 ICAM-1、CCL-2、CCL-7、MMP-2 和 MMP-9）的表达中观察到与酒精相关的增加（1.5-3.0 倍）。此外，酒精性肝损伤与肝脏定位改变以及结直肠癌细胞释放的 CEA 循环水平增加有关。总而言之，这些发现表明酒精肝可能通过 CEA 相关炎症机制为 CRLM 的建立提供了宽松的环境。
Metastatic liver disease is a major cause of mortality in colorectal cancer (CRC) patients. Alcohol consumption is a noted risk factor for secondary cancers yet the role of alcoholic liver disease (ALD) in colorectal liver metastases (CRLM) is not defined. This work evaluated tumor cell colonization in the alcoholic host liver using a novel preclinical model of human CRC liver metastases. Immunocompromised Rag1-deficient mice were fed either ethanol (E) or isocaloric control (C) diets for 4 weeks prior to intrasplenic injection of LS174T human CRC cells. ALD and CRLM were evaluated 3 or 5 weeks post-LS174T cell injection with continued C/E diet administration. ALD was confirmed by increased serum transaminases, hepatic steatosis and expression of cytochrome P4502E1, a major ethanol-metabolizing enzyme. Alcohol-mediated liver dysfunction was validated by impaired endocytosis of asialoorosomucoid and carcinoembryonic antigen (CEA), indicators of hepatocellular injury and progressive CRC disease, respectively. Strikingly, the rate and burden of CRLM was distinctly enhanced in alcoholic livers with metastases observed earlier and more severely in E-fed mice. Further, alcohol-related increases (1.5-3.0 fold) were observed in the expression of hepatic cytokines (TNF-alpha, IL-1 beta, IL-6, IL-10) and other factors noted to be involved in the colonization of CRC cells including ICAM-1, CCL-2, CCL-7, MMP-2, and MMP-9. Also, alcoholic liver injury was associated with altered hepatic localization as well as increased circulating levels of CEA released from CRC cells. Altogether, these findings indicate that the alcoholic liver provides a permissive environment for the establishment of CRLM, possibly through CEA-related inflammatory mechanisms.