Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China; Minimal Invasion Therapy Department 1, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
Cancer Lett. 2014 Oct 1;352(2):160-8. doi: 10.1016/j.canlet.2014.05.008. Epub 2014 Jun 2.
Tumor-associated macrophages (TAMs), a crucial component of immune cells infiltrated in tumor microenvironment, have been found to be associated with progression and metastasis of hepatocellular carcinoma (HCC). In this study, we aimed to clarify the mechanism underlying the crosstalk between TAMs and cancer stem cells (CSCs) in HCC. Mouse macrophage cell line RAW264.7 cells were used to investigate the effects of TAMs on mouse hepatoma cell line Hepa1-6 cells in vivo and vitro. A total of 90 clinical samples had pathology-proven HCC were used to evaluate the distribution of TAMs and CSCs and analyze their value in predicting the prognosis. In the study, we have found that the number of TAMs has a positive correlation with the density of CSCs in the marginal of human HCC. Our results show that, cocultured with TAM-conditioned medium (CM) promoted CSC-like properties in Hepa1-6 cells, which underwent EMT and gained higher invasive capability. TAMs secreted more transforming growth factor- beta1 (TGF-beta1) than other phenotypes of macrophage. Furthermore, depletion of TGF-beta1 blocked acquisition of CSC-like properties by inhibition of TGF-beta1-induced EMT. High expression of CD68 in the EpCAM positive expression HCC tissues was strongly associated with both poor cancer-free survival and overall survival in patients. Our results indicate that the TAMs promote CSC-like properties via TGF-beta1-induced EMT and they may contribute to investigate the prognosis of HCC.
肿瘤相关巨噬细胞（TAMs）是肿瘤微环境中浸润的免疫细胞的重要组成部分，已被发现与肝细胞癌（HCC）的进展和转移有关。在这项研究中，我们旨在阐明 TAMs 与 HCC 中的癌症干细胞（CSC）之间相互作用的机制。使用小鼠巨噬细胞 RAW264.7 细胞在体内和体外研究 TAMs 对小鼠肝癌细胞系 Hepa1-6 细胞的影响。共使用了 90 份经病理证实的 HCC 临床样本，评估 TAMs 和 CSCs 的分布，并分析其在预测预后中的价值。在研究中，我们发现 TAMs 的数量与 HCC 边缘 CSCs 的密度呈正相关。我们的结果表明，与 TAM 条件培养基（CM）共培养可促进 Hepa1-6 细胞中的 CSC 样特性，使其发生上皮间质转化（EMT）并获得更高的侵袭能力。TAMs 分泌的转化生长因子-β1（TGF-β1）比其他巨噬细胞表型更多。此外，TGF-β1 的耗竭通过抑制 TGF-β1 诱导的 EMT 阻断了 CSC 样特性的获得。在 EpCAM 阳性表达的 HCC 组织中，CD68 的高表达与患者无癌生存和总生存均较差密切相关。我们的结果表明，TAMs 通过 TGF-β1 诱导的 EMT 促进 CSC 样特性，它们可能有助于研究 HCC 的预后。
