Abstract
Simple SummaryCancer stem cells (CSCs) are known to be highly resistant to conventional therapeutic approaches, such as chemotherapeutic drugs and radiation. Therefore, selectively targeting CSCs with specific markers or signaling pathways can be an effective therapeutic strategy for treating chemotherapy-resistant liver cancer. However, there is not enough information currently available to make a conclusive statement regarding hepatic CSC-specific signaling pathways and biomarkers. In present study, we provide an overview of the current knowledge on the specific surface markers and critical signaling pathways of hepatic CSC.The first report of cancer stem cell (CSC) from Bruce et al. has demonstrated the relatively rare population of stem-like cells in acute myeloid leukemia (AML). The discovery of leukemic CSCs prompted further identification of CSCs in multiple types of solid tumor. Recently, extensive research has attempted to identity CSCs in multiple types of solid tumors in the brain, colon, head and neck, liver, and lung. Based on these studies, we hypothesize that the initiation and progression of most malignant tumors rely largely on the CSC population. Recent studies indicated that stem cell-related markers or signaling pathways, such as aldehyde dehydrogenase (ALDH), CD133, epithelial cell adhesion molecule (EpCAM), Wnt/β-catenin signaling, and Notch signaling, contribute to the initiation and progression of various liver cancer types. Importantly, CSCs are markedly resistant to conventional therapeutic approaches and current targeted therapeutics. Therefore, it is believed that selectively targeting specific markers and/or signaling pathways of hepatic CSCs is an effective therapeutic strategy for treating chemotherapy-resistant liver cancer. Here, we provide an overview of the current knowledge on the hepatic CSC hypothesis and discuss the specific surface markers and critical signaling pathways involved in the development and maintenance of hepatic CSC subpopulations.
Highlights
Liver cancer is the sixth most frequently diagnosed solid tumor worldwide in 2018 [1] and the third leading cause of cancer-related deaths [2]
Ma et al discovered in their purified subpopulations that CD133+ aldehyde dehydrogenase (ALDH)+ cells are more tumorigenic than CD133+ ALDH− cells when grafted to mice [90]
Demonstrated enhanced expression of Hh signaling components (PTCH1, Sonic hedgehog (Shh), Gli1) in liver cancer tissues compared with non-cancer tissues; in addition, these expressions positively correlated with tumor progression [206]
Summary
Liver cancer is the sixth most frequently diagnosed solid tumor worldwide in 2018 [1] and the third leading cause of cancer-related deaths [2]. Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer, representing approximately 20% of patients [4]. Both HCC and ICC are extremely heterogeneous tumors at both the genetic and phenotypic level. Recent studies indicate that HCC, ICC, and HCC-CC are highly heterogeneous in terms of their cellular and molecular characteristics and contain a small subset of self-renewing cells preferentially expressing various stem cell markers [6,7,8,9]. A subset of ICCs expresses stem/progenitor cell-related markers, suggesting CSCs are a possible cell source for ICC [11,12,13,14]. There is not enough information currently available to make a conclusive statement regarding the cellular origin of hepatocarcinogenesis, and additional characteristics related to hepatic CSC-specific signaling pathways and markers remain to be elucidated
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