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)