Metastasis of Cancer Stem Cells Developed in the Microenvironment of Hepatocellular Carcinoma
Metastasis of Cancer Stem Cells Developed in the Microenvironment of Hepatocellular Carcinoma
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DOI：
10.3390/bioengineering6030073
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发表时间：
2019-09-01
影响因子：
4.6
通讯作者：
Seno, Masaharu
中科院分区：
文献类型：
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作者：
Afify, Said M.;Hassan, Ghmkin;Seno, Masaharu
恶性肿瘤的转移是指癌细胞从原发部位向周围和远处组织转移，是肿瘤治疗中最关键的问题。我们的研究小组在癌症来源细胞的条件培养基（CM）的存在下，从诱导多能干细胞（iPSCs）发展出癌症干细胞（CSCs）。CSCs的特点是在体内形成恶性肿瘤，然后转移。在本研究中，在肝细胞癌（HCC）细胞系Huh7细胞CM存在的情况下，小鼠iPSCs转化为CSCs。这些转化细胞（miPS-Huh7cm细胞）被建立为转移细胞。将生成的CSCs注射到裸鼠肝脏或脾脏。移植后约1个月切除肿瘤，对恶性肿瘤和转移性结节的原代培养细胞进行干性和转移性标志物评价，比较其差异。miPS- huh7cm细胞表现出转移潜能，在体内可有效形成伴肺和/或肝脏病变的恶性肿瘤，而注射的miPS则形成畸胎瘤。来源于恶性肿瘤和转移结节的原代培养细胞维持Nanog、Klf4和c-Myc等干细胞标志物的表达，并获得CD90、CD44和ALDH1等肿瘤干细胞标志物。同时，恶性肿瘤原代细胞中Slug、Twist1、vimentin等转移标志物的表达高于转移结节。iPSCs衍生的CSCs形成恶性肿瘤并具有高转移性，为研究转移机制提供了良好的动物模型。
Metastasis develops when cancer cells spread from the primary site of a malignant tumor to the surrounding and distant tissues, and it is the most critical problem in cancer treatment. Our group developed cancer stem cells (CSCs) from induced pluripotent stem cells (iPSCs) in the presence of a conditioned medium (CM) of cancer-derived cells. The CSCs were characterized by the formation of malignant tumors in vivo, followed by metastasis. In this study, CSCs converted from mouse iPSCs in the presence of CM from hepatocellular carcinoma (HCC) cell line Huh7 cells. These converted cells (miPS-Huh7cm cells) were established as the metastatic cells. The generated CSCs were injected into the liver or spleen of nude mice. Almost one month after transplantation, the tumors were excised, and the primary cultured cells derived from the malignant tumors and metastatic nodules were evaluated by stemness and metastatic markers to compare their differences. The miPS-Huh7cm cells exhibited metastatic potential, and efficiently formed malignant tumors with lung and/or liver lesions in vivo, whereas the injected miPS formed teratoma. The primary cultured cells derived from the malignant tumors and metastatic nodules sustained the expression of stemness markers, such as Nanog, Klf4 and c-Myc, and acquired cancer stem markers, such as CD90, CD44 and ALDH1. Simultaneously, the expression of metastatic markers, such as Slug, Twist1 and vimentin, in primary cells derived from the malignant tumors, was higher than in metastatic nodules. The CSCs derived from iPSCs, forming malignant tumors and displaying high metastasis, will provide a good animal model to study the mechanisms of metastasis.