Hierarchical potential differentiation of liver cancer stem cells

Abstract

Hepatocellular carcinoma (HCC) is one of the most malignant tumors in Chinese people and offers poor prognosis. Tumor tissue, like normal tissue, is hierarchically differentiated. Thus, minor tumor cell populations able to differentiate, such as stem cells, sustain tumor self-renewal and proliferation. The fact that liver cancer stem cells (CSCs) with different surface markers appear heterogeneous with respect to oncogenesis and drug resistance indicates that subpopulations of surface markers preserve the hierarchical potential of differentiation during proliferation, deterioration and relapse. The epithelial to mesenchymal transition (EMT) is correlated to tumor malignancy and aggression, and hepatocytes bearing EMT have obvious hierarchical differentiation potential with respect to signaling pathways such as transforming growth factor β, Wnt/β-catenin and microRNA. Therefore, it may be more effective for early diagnosis to monitor HCC recurrence using peripherally circulating CSCs, and these may also offer potential for HCC immunotherapy or for targeting HCC treatment using these markers. Thus, we reviewed the generation, hierarchical differentiation and clinical application of hepatic CSCs.

Generation and characterization of hepatocellular carcinoma cell lines with enhanced cancer stem cell potential

“…Hepatic cancer stem cells are considered as the tumour initiating and heterogeneity promoting HCC cell populations . Besides their role in tumour formation and malignant tissue maintenance, HCSCs have also been reported to be involved in tumour progression, metastatis related processes and drug resistances, thereby largely contributing to HCC recurrences and therapy failure .…”

“…In addition to tumour initiation and continuous tumour growth, hepatic cancer stem cells (HCSCs) are also thought to be responsible for tumour progression and metastatic spread. They are resistant to conventional chemo‐ or radiotherapy and remain in the healthy tissue after surgical resection of primary tumours, thus being majorly responsible for HCC recurrences . However, the specific roles of HCSCs and the mechanisms by which they act during individual stages of tumour growth and progression are still poorly understood.…”

“…Within the frame of current CSC research numerous markers including the cell surface proteins CD133 and CD90, the detoxifying enzyme aldehyde dehydrogenase (ALDH) or the epithelial cell adhesion molecule (EpCAM) have been identified and correlated with certain stem cell characteristics. Although distinct combinations of markers could be linked to specific aggressive HCSC sub‐populations using both in vitro and in vivo studies, so far it remains a major challenge to identify reliable CSC‐specific biomarker sets that can eventually be applied in a clinical setting to improve HCC diagnosis and treatment strategies …”

“…These include unlimited self-renewal capacity and the ability to differentiate into multiple tumour cell subtypes, which contributes to tumour heterogeneity. 1,[12][13][14][15][16] In addition to tumour initiation and continuous tumour growth, hepatic cancer stem cells (HCSCs) are also thought to be responsible for tumour progression and metastatic spread. They are resistant to conventional chemo-or radiotherapy and remain in the healthy tissue after surgical resection of primary tumours, thus being majorly responsible for HCC recurrences.…”

“…They are resistant to conventional chemo-or radiotherapy and remain in the healthy tissue after surgical resection of primary tumours, thus being majorly responsible for HCC recurrences. 1,[15][16][17][18] However, the specific roles of HCSCs and the mechanisms by which they act during individual stages of tumour growth and progression are still poorly understood. This hinders the development of efficacious HCSC-targeting therapies for HCC patients that would eradicate CSC populations and promote a better patient outcome.…”