Epithelial-to-mesenchymal transition of murine liver tumor cells promotes invasion.
Epithelial-to-mesenchymal transition of murine liver tumor cells promotes invasion.
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DOI：
10.1002/hep.23748
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发表时间：
2010-09
期刊：
影响因子：
13.5
通讯作者：
Rountree, C. Bart
中科院分区：
文献类型：
--
作者：
Ding, Wei;You, Hanning;Dang, Hien;LeBlanc, Francis;Galicia, Vivian;Lu, Shelly C.;Stiles, Bangyan;Rountree, C. Bart
上皮 - 间质转化（EMT）预计在肝细胞癌的转移性疾病中起关键作用。在本研究中，我们使用一种新的EMT小鼠模型来阐明肿瘤进展和转移的机制。从Ptenloxp/loxp/Alb - Cre⁺小鼠中分离出总共2×10⁶个肝细胞，这些细胞是从单个CD133⁺CD45⁻细胞克隆扩增而来，为第0代（P0），依次移植以获得两代肿瘤细胞，P1和P2。使用微阵列和实时聚合酶链反应分析细胞的基因表达。功能分析包括体外的细胞增殖、迁移和侵袭以及体内的原位肿瘤转移实验。尽管P0、P1和P2各自都形成了与混合肝上皮一致的肿瘤，但在P2细胞内，两种不同的细胞类型清晰可见：具有与P0细胞相似上皮形态的细胞和具有成纤维细胞样形态的细胞。这些P2间质细胞在伤口愈合实验中表现出更强的运动能力；在基质胶基底膜上的细胞侵袭能力增强；Snail1、Zeb1和Zeb2等EMT相关基因表达增加；并且E - 钙黏蛋白下调。与P2上皮细胞相比，P2间质细胞在体内表现出明显更快的肿瘤生长速度，并侵袭肠道、胰腺、脾脏和淋巴结。此外，P2间质细胞分泌高水平的肝细胞生长因子（HGF），我们认为它以旁分泌的方式促使上皮细胞发生EMT。另外，一种缺乏甲硫氨酸腺苷转移酶1a的第二种小鼠肝癌干细胞系在连续移植后也发生了EMT，这表明EMT并不局限于Pten缺失的肿瘤。
EMT与体内肝脏肿瘤的高增殖率、侵袭和转移相关，这是由间质肿瘤细胞分泌的HGF以前馈机制驱动的。
Epithelial-to-mesenchymal transition (EMT) is predicted to play a critical role in metastatic disease in hepatocellular carcinoma. In this study, we used a novel murine model of EMT to elucidate a mechanism of tumor progression and metastasis. A total of 2 × 106 liver cells isolated from Ptenloxp/loxp/Alb-Cre+ mice, expanded from a single CD133+CD45− cell clone, passage 0 (P0), were sequentially transplanted to obtain two passages of tumor cells, P1 and P2. Cells were analyzed for gene expression using microarray and real-time polymerase chain reaction. Functional analysis included cell proliferation, migration, and invasion in vitro and orthotopic tumor metastasis assays in vivo. Although P0, P1, and P2 each formed tumors consistent with mixed liver epithelium, within the P2 cells, two distinct cell types were clearly visible: cells with epithelial morphology similar to P0 cells and cells with fibroblastoid morphology. These P2 mesenchymal cells demonstrated increased locomotion on wound healing; increased cell invasion on Matrigel basement membrane; increased EMT-associated gene expression of Snail1, Zeb1, and Zeb2; and down-regulated E-cadherin. P2 mesenchymal cells demonstrated significantly faster tumor growth in vivo compared with P2 epithelial counterparts, with invasion of intestine, pancreas, spleen, and lymph nodes. Furthermore, P2 mesenchymal cells secreted high levels of hepatocyte growth factor (HGF), which we propose acts in a paracrine fashion to drive epithelial cells to undergo EMT. In addition, a second murine liver cancer stem cell line with methionine adenosyltransferase 1a deficiency acquired EMT after sequential transplantations, indicating that EMT was not restricted to Pten-deleted tumors. EMT is associated with a high rate of liver tumor proliferation, invasion, and metastasis in vivo, which is driven by HGF secreted from mesenchymal tumor cells in a feed-forward mechanism.
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影响因子：
3.8
作者：
Matsuo N;Shiraha H;Fujikawa T;Takaoka N;Ueda N;Tanaka S;Nishina S;Nakanishi Y;Uemura M;Takaki A;Nakamura S;Kobayashi Y;Nouso K;Yagi T;Yamamoto K
通讯作者：
Yamamoto K
影响因子：
6
作者：
del Castillo, Gaelle;Factor, Valentina M.;Sanchez, Aranzazu
通讯作者：
Sanchez, Aranzazu
影响因子：
4
作者：
Nakanishi, K;Fujimoto, J;Okamoto, E
通讯作者：
Okamoto, E
影响因子：
3
作者：
Poon, RTP;Ng, IOL;Wong, J
通讯作者：
Wong, J
影响因子：
11.2
作者：
Chaffer, Christine L.;Brennan, Janelle P.;Williams, Elizabeth D.
通讯作者：
Williams, Elizabeth D.