A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelial-mesenchymal transition-independent manner
A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelial-mesenchymal transition-independent manner
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一种新的血管模式以不依赖上皮间质转化的方式促进肝细胞癌的转移
DOI：
10.1002/hep.27760
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发表时间：
2015-08-01
期刊：
影响因子：
13.5
通讯作者：
Zhuang, Shi-Mei
中科院分区：
文献类型：
--
作者：
Fang, Jian-Hong;Zhou, Hui-Chao;Zhuang, Shi-Mei
早期转移是肝细胞癌频繁复发和高死亡率的原因，但其潜在机制尚不清楚。上皮-间充质转化(EMT)被认为是肿瘤转移的关键事件。基于连续切片的组织学检查和三维重建，我们发现了一种新的普遍存在的血管模式，即包裹肿瘤簇并形成蛛网状网络的血管。VETC(VETC+)的存在预示着更高的肝癌转移和复发率。利用临床标本和小鼠异种移植模型，我们进一步证明，在肝癌早期，VETC是由有血液灌流的功能性血管组成的，并由肿瘤细胞诱导。随后的研究表明，肝癌细胞来源的血管生成素-2是VETC形成的先决条件，VETC模式是促进肝癌转移的关键因素，因为血管生成素-2的敲除消除了这种血管模式，从而减弱了体内肿瘤的转移。有趣的是，通过敲除Snail或Slug来取消EMT显著减少了VETC-异种移植瘤的体内转移，但对VETC+移植瘤的转移没有影响，尽管Snail或Slug的沉默显著减少了VETC+和VETC-HCC细胞的体外迁移。与人类VETC-病例相比，在VETC+有转移潜力的病例中很少观察到EMT征象。进一步的分析表明，VETC通过促进整个肿瘤簇释放到血流中，提供了一种有效的转移模式。结论：我们的发现发现了一种新的转移机制，这种转移机制依赖于血管类型，但不依赖于EMT，这可能为抗转移治疗提供新的靶点，并为选择可能受益于某些分子靶向药物的患者提供依据。(《肝病》2015；62：452-465
Early metastasis is responsible for frequent relapse and high mortality of hepatocellular carcinoma (HCC), but its underlying mechanisms remain unclear. Epithelial-mesenchymal transition (EMT) has been considered a key event in metastasis. Based on histological examination of serial HCC sections and three-dimensional reconstruction, we found a novel and prevalent vascular pattern, vessels that encapsulated tumor clusters (VETC) and formed cobweb-like networks. The presence of VETC (VETC+) predicted higher metastasis and recurrence rates of HCC. Using clinical samples and mouse xenograft models, we further showed that VETC was composed of functional vessels with blood perfusion and induced by tumor cells at the early stage of HCC. Subsequent investigations revealed that HCC cell-derived angiopoietin-2 was a prerequisite for VETC formation and that the VETC pattern was a critical factor promoting HCC metastasis as knockdown of angiopoietin-2 abolished this vascular pattern and consequently attenuated in vivo tumor metastasis. Interestingly, abrogation of EMT by knockdown of Snail or Slug significantly diminished in vivo metastasis of VETC- xenografts but did not affect that of VETC+ ones, although silencing of Snail or Slug substantially reduced the in vitro migration of both VETC+ and VETC- HCC cells. In contrast to human VETC- cases, EMT signatures were rarely observed in VETC+ cases with metastatic potential. Further analysis revealed that VETC provided an efficient metastasis mode by facilitating the release of whole tumor clusters into the bloodstream. Conclusion: Our findings identify a novel metastasis mechanism that relies on vascular pattern but is independent of EMT, which may provide new targets for antimetastasis therapy and offer a basis for selecting patients who may benefit from certain molecularly targeted drugs. (Hepatology 2015;62:452-465