Attenuated liver tumor formation in the absence of CCR2 with a concomitant reduction in the accumulation of hepatic stellate cells, macrophages and neovascularization
Attenuated liver tumor formation in the absence of CCR2 with a concomitant reduction in the accumulation of hepatic stellate cells, macrophages and neovascularization
复制标题
DOI：
10.1002/ijc.21371
复制
发表时间：
2006-01
影响因子：
6.4
通讯作者：
Xiaoqin Yang;P. Lu;Y. Ishida;W. Kuziel;C. Fujii;N. Mukaida
中科院分区：
文献类型：
--
作者：
Xiaoqin Yang;P. Lu;Y. Ishida;W. Kuziel;C. Fujii;N. Mukaida
肝实质由肝细胞和几种非实质细胞类型组成，包括枯否细胞和肝星状细胞。枯否细胞和肝星状细胞都对趋化因子CCL2有反应，但CCL2和这些细胞在肝肿瘤形成中的确切作用仍不清楚。因此，我们研究了缺乏主要的CCL2受体CCR2对门静脉内注射小鼠结肠腺癌细胞系结肠26诱导的肝肿瘤形成的影响。注射结肠26细胞后10天，野生型小鼠在肝脏中显示肉眼可见的肿瘤病灶。10天后，CCL2蛋白主要在肿瘤细胞中检测到，与肿瘤内巨噬细胞和肝星状细胞数量增加一致。尽管在肿瘤细胞注射后10天内，野生型和CCR 2缺陷型小鼠的肿瘤形成率相似，但此后CCR 2缺陷型小鼠的肿瘤病灶数量和大小相对于野生型小鼠显著减弱。此外，CCR2缺陷小鼠中的新血管形成和基质金属蛋白酶2表达减少，同时巨噬细胞和肝星状细胞蓄积减少。此外，基质金属蛋白酶2主要在肝星状细胞中检测到，而不是在巨噬细胞中。我们提供了第一个明确的证据，证明CCR2介导的信号的缺乏可以减少肝星状细胞的运输，这是基质金属蛋白酶2的主要来源，因此可以减少肝脏肿瘤形成期间的新血管形成。© 2005 Wiley利斯公司
The liver parenchyma is populated by hepatocytes and several nonparenchymal cell types, including Kupffer cells and hepatic stellate cells. Both Kupffer cells and hepatic stellate cells are responsive to the chemokine CCL2, but the precise roles of CCL2 and these cells in liver tumor formation remain undefined. Hence, we investigated the effects of the lack of the major CCL2 receptor, CCR2, on liver tumor formation induced by intraportal injection of the murine colon adenocarcinoma cell line, colon 26. Wild‐type mice showed macroscopic tumor foci in the liver 10 days after injection of colon 26 cells. After 10 days, CCL2 proteins were detected predominantly in tumor cells, coincident with increased intratumoral macrophage and hepatic stellate cell numbers. Although tumor formation occurred at similar rates in wild‐type and CCR2‐deficient mice up to 10 days after tumor cell injection, the number and size of tumor foci were significantly attenuated in CCR2‐deficient mice relative to wild‐type mice thereafter. Moreover, neovascularization and matrix metalloproteinase 2 expression were diminished in CCR2‐deficient mice with a concomitant reduction in the accumulation of macrophages and hepatic stellate cells. Furthermore, matrix metalloproteinase 2 was detected predominantly in hepatic stellate cells but not in macrophages. We provided the first definitive evidence that the absence of CCR2‐mediated signals can reduce the trafficking of hepatic stellate cells, a main source of matrix metalloproteinase 2, and consequently can diminish neovascularization during liver tumor formation. © 2005 Wiley‐Liss, Inc.