Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4258, USA.
Int J Biol Sci. 2011 Apr 26;7(5):517-35. doi: 10.7150/ijbs.7.517.
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.
癌症干细胞 (CSC) 假说最早在 40 多年前提出。CSC 的分离技术最初在血液恶性肿瘤中取得突破，第一个 CSC 在急性髓性白血病中得到证实。然而，利用类似的策略和技术，并利用现有的表面标记物，最近在越来越多的上皮和其他实体器官恶性肿瘤中也证实了 CSCs 的存在，这表明大多数恶性肿瘤都依赖于这样的细胞群体。原发性肝癌主要由肝细胞癌 (HCC) 和肝内胆管癌 (ICC) 组成。据信肝祖细胞 (HPC) 可能是某些 HCC 和 ICC 的起源。此外，Wnt/β-catenin、TGF-β、Notch 和 Hedgehog 信号通路等干细胞激活剂也加速了肿瘤的发生，这些通路可以作为分子靶点，有助于设计癌症预防策略。最近的研究表明，EpCAM、Lin28 或 miR-181 等其他因素也可能通过靶向 HCC CSCs 促进 HCC 的进展。各种直接调节 CSCs 的治疗药物已在体内和体外进行了研究。然而，CSC 的发病机制显然很复杂，信号通路之间存在着相当大的串扰和冗余，因此针对单个分子或通路进行治疗可能效果有限。许多关键的信号分子在 CSCs 和正常干细胞中都有表达，这为设计针对 CSCs 但不影响正常干细胞的分子靶向策略增加了进一步的挑战，以避免副作用。在设计 HCC 的治疗策略时，除了直接控制 CSCs 外，还需要考虑许多其他维持 CSCs 所需的因素，如血管生成、血管生成、侵袭和迁移、缺氧、免疫逃避、多药耐药和放射抵抗等。在这里，我们简要综述了肝 CSCs 的分子信号，并提出了针对肝 CSCs 的新治疗策略的见解。
