Elsevier

Experimental Cell Research

Volume 319, Issue 2, 15 January 2013, Pages 126-132
Experimental Cell Research

Review Article
Biology and clinical implications of CD133+ liver cancer stem cells

https://doi.org/10.1016/j.yexcr.2012.09.007Get rights and content

Abstract

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver, accounting for 80%–90% of all liver cancers. The disease ranks as the fifth most common cancer worldwide and is the third leading cause of all cancer-associated deaths. Although advances in HCC detection and treatment have increased the likelihood of a cure at early stages of the disease, HCC remains largely incurable because of late presentation and tumor recurrence. Only 25% of HCC patients are deemed suitable for curative treatment, with the overall survival at just a few months for inoperable patients. Apart from surgical resection, loco-regional ablation and liver transplantation, current treatment protocols include conventional cytotoxic chemotherapy. But due to the highly resistant nature of the disease, the efficacy of the latter regimen is limited. The recent emergence of the cancer stem cell (CSC) concept lends insight into the explanation of why treatment with chemotherapy often may seem to be initially successful but results in not only a failure to eradicate the tumor but also possibly tumor relapse. Commonly used anti-cancer drugs in HCC work by targeting the rapidly proliferating and differentiated liver cancer cells that constitute the bulk of the tumor. However, a subset of CSCs exists within the tumor, which are more resistant and are able to survive and maintain residence after treatment, thus, growing and self-renewing to generate the development and spread of recurrent tumors in HCC. In the past few years, compelling evidence has emerged in support of the hierarchic CSC model for solid tumors, including HCC. And in particular, CD133 has drawn significant attention as a critical liver CSC marker. Understanding the characteristics and function of CD133+ liver CSCs has also shed light on HCC management and treatment, including the implications for prognosis, prediction and treatment resistance. In this review, a detailed summary of the recent progress in CD133+ liver CSC research with regard to identification, regulation and clinical implications will be discussed.

Section snippets

Cancer stem cells

Cancer is hierarchically organized and composed of a heterogeneous population of cells, among which researchers have now provided solid evidence of the existence and importance of a cancer stem cell (CSC) subpopulation. Other commonly used terms for “cancer stem cells” include “tumor-initiating cells” and “cancer-initiating cells”; all referring to the same compartment of cells in a tumor that bears both cancer and stem cell-like properties. CSCs are now defined as a group of cells having the

The CD133 molecule

CD133 was the first identified member of the prominin family of pentaspan transmembrane glycoprotein (5-transmembrane). It is also commonly known in humans and rodents as Prominin 1 (PROM1) [1]. The specific function and ligands of CD133 are still largely unknown, but they are known to be distinct in their restricted localization to cellular/plasma membrane protrusions. CD133 was first found as a marker of primitive hematopoietic stem and progenitor cells [2] and then later also found to

CD133 as a marker of primary and metastastic liver cancer stem cells

Following the early attempts to isolate CSCs in hepatocellular carcinoma (HCC) through identification of a side population (SP) using the DNA-binding dye Hoechst 33342 in 2006 by two independent Japanese group of researchers [4], [5], significant efforts have been made to further characterize CSCs of this deadly disease. In particular, CD133 has drawn momentous attention as an important liver CSC marker. CD133+ cells were first reported to mark a CSC subset in HCC by Suetsugu et al. [6]. In

Expression and clinical significance of CD133 in liver cancer

By immunohistochemical analysis, CD133 has now been consistently reported in several independent studies to be localized on both the membrane and cytoplasm. Pattern of CD133 staining is random, mostly scattered but occasionally distributed in clusters. The first study to report the expression of CD133 in human HCC tissue samples was carried out by Yin et al. in 2007. By immunohistochemistry, the authors found CD133 to be frequently detected at low levels (0.1%–1%) in HCC or cirrhotic liver

Aberrant signaling pathways in CD133+ liver cancer stem cells

Considerable advances over the last several years have unraveled key molecular mechanisms of hepatocarcinogenesis driven specifically by CD133+ liver CSCs. Studies from our research group have found CD133+ liver CSCs to confer chemoresistance via preferential activation of the Akt and Bcl-2 survival pathway [10] and that CD133+ liver CSCs to promote tumor angiogenesis, growth and self-renewal through a deregulated neurotensin-induced IL-8/CXCL1 signaling cascade [15]. We also found a number of

Functional role of CD133 in liver cancer

In addition to the study of sorted CD133 subpopulations and their deregulated signaling pathways in HCC, two recent studies have also focused on examining whether CD133 is simply a marker of liver CSCs or whether it also carries a functional role. Using lentiviral-based shRNA approach, our group recently found stable knockdown of CD133 in PLC8024 HCC cells to have a significant reduction in the cells' ability to self-renew and initiate tumor growth, as demonstrated by spheroid formation assay

Epigenetic regulation of CD133 in liver cancer

The importance of epigenetics has widely been reported in liver cancer. Changes in the DNA methylation patterns, including global hypomethylation and promoter hypermethylation are established as frequent and early events during human liver oncogenesis. Work in the epigenetic regulation of CD133 has been reported in a number of different cancer types including colon cancer, ovarian cancer and glioblastoma. However, epigenetic regulation of CD133 in HCC has been very limited. Two recent reports

MicroRNA deregulation in CD133+ liver cancer stem cells

MicroRNAs (miRNAs) have been implicated in the maintenance of CSC phenotype via their ability to affect expression of genes and proteins that regulate cancer and stem cell-like features. To date, there have been two reports documenting the role of deregulated miRNAs in CD133+ versus CD133− cells and their role in the maintenance of a CD133+ liver CSC phenotype. Our group was the first to report the role of deregulated miRNAs in regulation of liver CSCs. Specifically, through profiling isolated

Induction of CD133 liver cancer stem cells by hepatitis B and C virus

Chronic hepatitis viral infection (HBV and HCV) are two of the most important etiological factors for HCC. Over 90% of HCC patients also either has HBV or HCV infection. Epidemiological studies have shown that the relative risk of HCC among HBV or HCV carriers is 10-fold higher than that of non-carriers. Thus, understanding the mechanism by which HBV or HCV induces HCC formation is of critical importance. A recent study by Ali et al. found expression of an HCV subgenomic replicon in culture

Therapeutic implications and outstanding challenges

Implicit in the CSC hypothesis is the belief that cancer initiation, progression, recurrence, metastasis and therapy resistance are the key unique elements of CSC subsets. Thus, consequently, targeting CSCs should bring about important therapeutic implications. Current clinical treatment strategies are developed to target by large only the bulk rapidly proliferating tumor cells and also likely the differentiated tumor cells. Though these treatments seem to be initially successful, effects are

Acknowledgments

Liver cancer stem cell studies in the laboratory is generously supported by grants from the Research Grant Council—General Research Fund (HKU 760911M and HKU 773412M), Research Grant Council—Collaborative Research Fund (CUHK8/CRF/11R, HKU3/CRF/11R and HKU7/CRF/09), the University of Hong Kong Strategic Research Theme in Cancer and the University of Hong Kong Seed Fund Programme for Basic Research.

References (33)

  • T. Chiba et al.

    Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties

    Hepatology

    (2006)
  • S. Yin et al.

    CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity

    Int. J. Cancer

    (2007)
  • S. Ma et al.

    CD133+HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

    Oncogene

    (2008)
  • T. Yamashita et al.

    EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features

    Gastroenterology

    (2009)
  • Z. Zhu et al.

    Cancer stem/progenitor cells are highly enriched in CD133+CD44+ population in hepatocellular carcinoma

    Int. J. Cancer

    (2010)
  • Y. Hou et al.

    The critical role of CD133(+)CD44(+/high) tumor cells in hematogenous metastasis of liver cancers

    Cell Res.

    (2012)

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