Hepatic Stellate Cells Promote Liver Metastasis of Colon Cancer Cells by the Action of SDF-1/CXCR4 Axis
Hepatic Stellate Cells Promote Liver Metastasis of Colon Cancer Cells by the Action of SDF-1/CXCR4 Axis
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DOI：
10.1245/s10434-009-0599-x
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发表时间：
2009-09-01
影响因子：
3.7
通讯作者：
Sakai, Yoshiharu
中科院分区：
文献类型：
--
作者：
Matsusue, Ryo;Kubo, Hajime;Sakai, Yoshiharu
背景。已经确定趋化因子受体CXCR4及其配体基质细胞衍生因子-1 （SDF-1）调节多种癌症的几个关键过程。然而，SDF-1/CXCR4系统在结直肠癌转移中的功能和机制仍存在争议。采用免疫组化方法定量检测40例人类结直肠癌和肝转移标本中CXCR4的表达。体外研究了SDF-1对HCT116结肠癌细胞的作用。我们用表达SDF-1的肝星状细胞（HSCs）皮下接种HCT116细胞。对CXCR4抑制剂AMD3100进行了体外和体内实验。通过对细胞数量的定量计数，我们发现肝脏转移部位的cxcr4阳性细胞多于原发部位。我们在体外证明了SDF-1对HCT116细胞的侵袭和抗凋亡的作用。在小鼠肝转移实验中，腹腔注射AMD3100可阻断HCT116细胞的转移潜能。此外，我们发现肝转移灶周围来源于造血干细胞的a-平滑肌肌动蛋白（α - sma）阳性肌成纤维细胞分泌SDF-1。HCT116细胞皮下接种造血干细胞可促进裸鼠体内肿瘤的发生，提示HCT116细胞与造血干细胞在体内直接相互作用的重要性。这些结果表明造血干细胞通过SDF-1/CXCR4轴的作用在结肠癌细胞肝转移中发挥重要作用，并为阻断该轴是抗转移治疗的靶点提供了临床前证据。
Background. It has been determined that the chemokine receptor CXCR4 and its ligand stromal cell-derived factor-1 (SDF-1) regulate several key processes in a wide variety of cancers. However, the function and mechanism of the SDF-1/CXCR4 system in the metastasis of colorectal cancer remain controversial.Methods. Immunohistochemistry was performed to examine quantitatively the expression of CXCR4 in 40 human samples of colorectal cancer and liver metastasis. The functions of SDF-1 on HCT116 colon cancer cells were investigated in vitro. We subcutaneously inoculated HCT116 cells with hepatic stellate cells (HSCs) expressing SDF-1. The CXCR4 inhibitor AMD3100 was tested in vitro and in vivo.Results. By quantitatively counting the number of cells, it was shown that there are more CXCR4-positive cells at the metastatic site in the liver compared with the primary sites. We demonstrated the effect of SDF-1 on the invasion and antiapoptosis of HCT116 cells in vitro. In mouse experiment of liver metastasis, intraperitoneal administration of AMD3100 blocked the metastatic potential of HCT116 cells. Furthermore, we found that a-smooth muscle actin (alpha-SMA)positive myofibroblasts derived from HSCs, surrounding the liver metastasis foci, secreted SDF-1. The subcutaneous inoculation of HCT116 cells with HSCs promoted the tumor initiation in nude mice, indicating the importance of the direct interaction between these cells in vivo.Conclusion. These results suggest that HSCs play important role in liver metastasis of colon cancer cells by the action of SDF-1/CXCR4 axis and provide preclinical evidence that blockade of the axis is a target for antimetastasis therapy.