Orchestration of hepatocellular carcinoma development by diverse liver cancer stem cells

Journal of Gastroenterology, Jul 2014

Hepatocellular carcinoma (HCC) is one of the world’s most aggressive diseases and carries a poor prognosis for patients. Recent evidence suggests that HCC is organized by cancer stem cells (CSCs), which are a subset of cells with stem cell-like features. CSCs are considered a pivotal target for the eradication of cancer, and liver CSCs have been investigated using various stem cell markers. Several hepatic stem/progenitor markers have been shown to be useful for isolating putative CSCs from HCC, although the expression patterns and phenotypic diversity of CSCs purified by these markers remain obscure. Recently, we found that liver CSCs defined by different markers show unique features of tumorigenicity and metastasis, with phenotypes closely associated with committed liver lineages. Furthermore, our data suggest that these distinct CSCs collaborate to orchestrate the tumorigenicity and metastasis of HCC. In this review article, we summarize the recent advances in understanding the pathogenesis and heterogeneity of liver CSCs.

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Orchestration of hepatocellular carcinoma development by diverse liver cancer stem cells

Taro Yamashita 0 1 Shuichi Kaneko 0 1 0 S. Kaneko Departments of Gastroenterology, Kanazawa University Hospital , Kanazawa, Ishikawa, Japan 1 T. Yamashita (&) Departments of General Medicine, Kanazawa University Hospital , Kanazawa, Ishikawa, Japan Hepatocellular carcinoma (HCC) is one of the world's most aggressive diseases and carries a poor prognosis for patients. Recent evidence suggests that HCC is organized by cancer stem cells (CSCs), which are a subset of cells with stem cell-like features. CSCs are considered a pivotal target for the eradication of cancer, and liver CSCs have been investigated using various stem cell markers. Several hepatic stem/progenitor markers have been shown to be useful for isolating putative CSCs from HCC, although the expression patterns and phenotypic diversity of CSCs purified by these markers remain obscure. Recently, we found that liver CSCs defined by different markers show unique features of tumorigenicity and metastasis, with phenotypes closely associated with committed liver lineages. Furthermore, our data suggest that these distinct CSCs collaborate to orchestrate the tumorigenicity and metastasis of HCC. In this review article, we summarize the recent advances in understanding the pathogenesis and heterogeneity of liver CSCs. - Cancer stem cell Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer worldwide [1]. Its prevalence is mostly attributed to hepatitis B virus or hepatitis C virus infection, and high incidence is observed in Asia and Africa [2]. Increasing occurrences and mortality from HCC have also been observed in most industrialized countries [3]. Therefore, there is an urgent need to develop effective diagnostic and treatment strategies against this disease. HCC is a heterogeneous disease in terms of morphology, biological behavior, response to treatment, and molecular profile [4]. This heterogeneity has traditionally been explained by the clonal evolution of tumor cells resulting from the progressive accumulation of multiple genetic and epigenetic changes [5, 6]. However, recent studies suggest that its heterogeneity may result from the hierarchical organization of tumor cells by a subset of cells with stem and progenitor cell features known as cancer stem cells (CSCs) [7]. CSCs are highly tumorigenic, metastatic, chemo- and radiotherapy resistant, responsible for tumor relapse after therapy, and able to divide symmetrically or asymmetrically to orchestrate the tumor mass [8]. Therefore, they are considered to be a pivotal target for eradicating HCC [9]. In this review, we summarize recent findings on liver CSCs in terms of heterogeneity and discuss an HCC treatment strategy that targets them. Cancer cells and stem cells have similar capabilities with respect to self-renewal, limitless division, and the generation of heterogeneous cell populations. The observation of these similarities many years ago led to the proposal that cancer might be a type of abnormal stem cell disease [10], a concept which has recently been revisited [11]. The generally acknowledged definition of a CSC is a cell within a tumor that possesses the ability to self-renew and to give rise to heterogeneous lineages of cancer cells that comprise tumors in immunodeficient mice [11]. Experimentally, putative CSCs have been isolated using cell surface markers specific for normal stem cells. Stem cell-like features of CSCs have been confirmed by functional in vitro clonogenicity and in vivo tumorigenicity assays. Moreover, accumulating evidence suggests that CSCs play a role in perpetuating various cancers including leukemia and solid tumors [1218]. In HCC, several markers are reported to enrich the CSC population, including the epithelial cell adhesion molecule (EpCAM), CD133, CD90, CD44, CD24, CD13, and oval cell marker OV6, as well as Hoechst dye efflux or aldehyde dehydrogenase activities [1925]. Most of these markers are expressed in normal hepatic progenitors known as oncofetal markers [2022, 2635]. These marker-positive cells were experimentally confirmed to be more tumorigenic than marker-negative cells in immunodeficient mice using cell lines [9]. Among them, calcium channel a2d1 isoform5, EpCAM, CD90, and CD133 are the markers confirmed thus far to enrich CSCs from primary HCCs [36, 37]. Recent studies have shown that some of these liver CSC markers are also functionally involved in the maintenance of CSC features (Table 1). EpCAM enhances Wnt signaling in ES cells and cancer [38, 39], and CD133 expression may maintain CD133? liver CSCs through the activation of neurotensin/IL-8/CXCL1 signaling [40]. CD44 regulates the redox status [41], while CD13 decreases cell damage induced by oxidative stress after exposure to genotoxic reagents [19]. Furthermore, a recent study demonstrated that the calcium channel a2d1 isoform5, recognized by a monoclonal antibody 1B50-1, is expressed in liver CSCs and regulates calcium influx and Table 1 Cell surface ma (...truncated)


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Taro Yamashita, Shuichi Kaneko. Orchestration of hepatocellular carcinoma development by diverse liver cancer stem cells, Journal of Gastroenterology, 2014, pp. 1105-1110, Volume 49, Issue 7, DOI: 10.1007/s00535-014-0951-1