Novel therapeutic strategies for targeting liver cancer stem cells.
Novel therapeutic strategies for targeting liver cancer stem cells.
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DOI：
10.7150/ijbs.7.517
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发表时间：
2011-04-26
影响因子：
9.2
通讯作者：
Wang XW
中科院分区：
文献类型：
--
作者：
Oishi N;Wang XW
癌症干细胞（CSC）假说是在40多年前首次提出的。CSC分离的进展首先在血液恶性肿瘤中实现，第一个CSC在急性髓性白血病中得到证实。然而，使用类似的策略和技术，并利用可用的表面标志物，CSC最近已被证明在越来越多的上皮和其他实体器官恶性肿瘤，这表明大多数恶性肿瘤依赖于这样的隔室。原发性肝癌主要包括肝细胞癌（HCC）和肝内胆管细胞癌（ICC）。肝祖细胞（hepatic progenitor cells，HPCs）可能是某些HCC和ICC的起源。此外，干细胞活化剂如Wnt/β-连环蛋白、TGF-β、Notch和Hedgehog信号通路也加速肿瘤发生，并且这些通路可以作为分子靶标来帮助设计癌症预防策略。最近的研究表明，其他因子如EpCAM、Lin 28或miR-181也可能通过靶向HCC CSC而促进HCC进展。已经在体内和体外检查了直接调节CSC的各种治疗药物。然而，CSC显然具有复杂的发病机制，在信号传导途径中具有相当大的串扰和冗余，因此靶向单个分子或途径可能对治疗具有有限的益处。许多关键信号分子由CSC和正常干细胞共享，这为设计特异于CSC的分子靶向策略增加了进一步的挑战，但保留正常干细胞以避免副作用。除了对CSC的直接控制外，在设计HCC的治疗策略时，还应考虑维持CSC所需的许多其他因素，如血管生成、血管发生、侵袭和迁移、缺氧、免疫逃避、多药耐药性和放射抗性。在这里，我们提供了一个简短的审查，在肝CSCs的分子信号，并提出新的治疗策略，靶向肝CSCs的见解。
The cancer stem cell (CSC) hypothesis was first proposed over 40 years ago. Advances in CSC isolation were first achieved in hematological malignancies, with the first CSC demonstrated in acute myeloid leukemia. However, using similar strategies and technologies, and taking advantage of available surface markers, CSCs have been more recently demonstrated in a growing range of epithelial and other solid organ malignancies, suggesting that the majority of malignancies are dependent on such a compartment. Primary liver cancer consists predominantly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). It is believed that hepatic progenitor cells (HPCs) could be the origin of some HCCs and ICCs. Furthermore, stem cell activators such as Wnt/β-catenin, TGF-β, Notch and Hedgehog signaling pathways also expedite tumorigenesis, and these pathways could serve as molecular targets to assist in designing cancer prevention strategies. Recent studies indicate that additional factors such as EpCAM, Lin28 or miR-181 may also contribute to HCC progression by targeting HCC CSCs. Various therapeutic drugs that directly modulate CSCs have been examined in vivo and in vitro. However, CSCs clearly have a complex pathogenesis, with a considerable crosstalk and redundancy in signaling pathways, and hence targeting single molecules or pathways may have a limited benefit for treatment. Many of the key signaling molecules are shared by both CSCs and normal stem cells, which add further challenges for designing molecularly targeted strategies specific to CSCs but sparing normal stem cells to avoid side effects. In addition to the direct control of CSCs, many other factors that are needed for the maintenance of CSCs, such as angiogenesis, vasculogenesis, invasion and migration, hypoxia, immune evasion, multiple drug resistance, and radioresistance, should be taken into consideration when designing therapeutic strategies for HCC. Here we provide a brief review of molecular signaling in liver CSCs and present insights into new therapeutic strategies for targeting liver CSCs.
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作者：
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