Research Article: The Recent Advances on Liver Cancer Stem Cells: Biomarkers, Separation, and Therapy

Date Published: July 27, 2017

Publisher: Hindawi

Author(s): Yanhong Xiao, Mei Lin, Xingmao Jiang, Jun Ye, Ting Guo, Yujuan Shi, Xuefeng Bian.


As the third major reason of mortality related to cancer in the world, liver cancer is also the fifth most frequent cancer. Unluckily, a majority of patients succumb and relapse though many progresses have been made in detection and therapy of liver cancer. It has been put forward that in liver cancer, cancer stem cells (CSCs) hold main responsibility for the formation, invasion, metastasis, and recurrence of tumor. Strategies that are intended to target liver CSCs are playing a more and more significant role in supervising the development of liver cancer treatment and assessing new therapeutic methods. Herein, a brief review about molecule markers, signal pathways, separation, and treatment on liver cancer stem cells (LCSCs) is provided in this paper.

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As a malignant tumor, the hepatocellular carcinoma (HCC) frequently occurs in the world, which severely threatens the health and life of human beings [1]. It is reported that over six hundred thousand people die of HCC every year. Nonalcoholic obesity liver disease, alcohol abuse, and hepatitis virus are main risk factors leading to liver cancer [2]. Currently, transcatheter arterial chemoembolization (TACE), liver transplantation, surgical treatment, radiofrequency ablation (RFA), radiotherapy, and chemotherapy are traditional therapies of HCC, but these therapies have poor effect for patients at advanced phase, metastasis, or recurrence. It has been popular to seek new approach to treat intermediate, advanced HCC in the past ten years. Recently, the theory of cancer stem cell (CSCs) offers a new idea for prognosis, diagnosis, and treatment for HCC.

A great number of LCSC surface markers such as ALDH, CD133, CD13, CD90, CD44, CD24, OV6, and EpCAM have been found, and new surface markers of LCSC are constantly identified and discussed.

A great deal of research has proved that Notch, Wnt/β-catenin, hedgehog, and TGF-β signaling network are implicated in maintaining the tissue homeostasis by adjusting the self-renewal ability of normal stem cells as well as proliferation or differentiation degree of progenitor cells. Particularly, the importance of Wnt/β-catenin and hedgehog signaling pathways for embryogenic development has been verified in the acquisition of EMT and the biology of CSCs. The transformation to CSC is caused by the breakage of the signaling network for normal stem cells. Because of genetic alteration or epigenetic change of stem cell signaling-related genes, CSC is caused by self-renewal potential in progenitor cells. The dysregulation of Notch, Wnt/β-catenin, hedgehog, and TGF-β signaling pathways in CSCs from numerous human tissues or organs should be investigated systematically so as to better understand CSCs and the corresponding role in carcinogenesis. During hepatocarcinogenesis process, dysregulation of signaling pathways was found and the signaling pathways of Wnt, TGF-β, hedgehog and Notch have been studied extensively.

To recognize and separate CSC so as to research their qualities accurately is quite significant. In order to characterize CSCs, various analytical approaches and skills have been adopted. Frequently used approaches for identifying and separating CSCs contain molecular, functional, image-based, cytologic arrangement, and percolation methods, the usage of various membrane markers and xenografts. LCSCs can be recognized and separated through 4 major methods: separation by flow cytometry on the basis of CSC-specific cell membrane markers [58, 59]; recognition of side population (SP) phenotype excluded by Hoechst 33342 assay [60]; decision of capability to develop as flowing balls in serum-free medium [61, 62]; and evaluation of aldehyde dehydrogenase (ALDH) liveness [63].

Even though ionizing radiation and chemotherapy wipe out tumor cells in the proliferative cell cycle, CSCs have native resistance to these therapies. Intervention with self-renewing, subsistence, and niche characteristics of CSC is a feasible tactic for targeted treatment.

In recent days, various markers were applied in the identification of LCSCs. Later, a number of deregulated molecular pathways had been found in LCSCs. In-depth research showed that the markers may make contribution to diagnosis, prognosis, and treatment in HCC patients. It was found by Yang et al. [18] that CD45−CD90+ cells could be found in all the samples of tumor, yet none in the parallel (normal and cirrhotic nontumorous livers). Besides, CD45−CD90+ cells could be detected in 90% of blood samples from patients with liver cancer, yet not in cirrhosis patients or normal subjects. CD45−CD90+ can serve as a target to diagnose and treat malignancy and as a marker for liver cancer in human beings according to the identification of CD45−CD90+ CSCs in circulation and tumor tissues. According to Piao et al. [76], the liver cancer cells of CD133 expression have radioresistance and antiapoptotic properties which can enhance anticancer therapies, such as radiotherapy/chemotherapy of HCC. According to Song et al. [4], reactivated CD133-positive cells can be commonly found in HCC. In addition, the higher stage of HCC tumors, the more expression of CD133, the poorer prognosis for patients.

The theory of CSCs in liver cancer of human beings can be supported by lots of evidences. The isolation and identification of LCSCs can be considered as a basic study. A number of markers, including CD13, CD44, CD24, CD133, CD90, EpCAM, and SP cell can be used to identify LCSCs. However, many critical problems still need to be found and solved. There is still not a consensus of an “international” marker for LCSCs. The amount of CSCs is different based on cell lines, and not all the isolated cells by CSC markers were CSCs. Besides, some of the pivotal markers which are important to CSCs can be shared by normal stem cells as well. Therefore, normal stem cells can be affected by drugs which target these markers in a negative way. Lots of data have shown that the deregulation of many signaling pathways are significant to CSC self-renewal, which can potentially be the targets for treatment. Further researches on the differential signaling pathways between CSCs and the amount of normal stem cell may decrease the negative impacts of drugs on the regeneration of normal tissue. Current study emphasizes on a novel generation of anticancer drugs which target different amounts of CSCs selectively. As researches on surface markers and relevant signaling pathways as well as molecular biology develop, new tumor-specific therapies may be applied to cure liver cancer patients in the future.




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