Cancer Stem Cells in
Nasopharyngeal Carcinoma: Current Evidence
Fenggang Yu1, Kwok Seng Loh2
of Otolaryngology, Yong Loo Lin School of Medicine, National University of
Neck Tumor Group, National Cancer Institute of Singapore, National University
Health System (NUHS), Singapore
author: Fenggang Yu; E-mail: firstname.lastname@example.org
Citation: Yu FG, Loh KS. Cancer stem cells in nasopharyngeal
carcinoma: current evidence. J Nasopharyng Carcinoma, 2014, 1(6): e6.
Funding: This work was supported by a Grant from the
National University Cancer Institute, Singapore (NCIS) Centre Grant to Dr.
Loh and Dr. Yu.
Competing interests: The authors have declared that no competing
Copyright: 2014 By the Editorial Department of Journal of
Nasopharyngeal Carcinoma. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
carcinoma (NPC) is highly prevalent in southern China and Southeast Asia.
Cancer resistance to therapy, metastasis and disease recurrence are significant
hurdles to successful treatment of NPC. Identifying mechanisms by which NPC is
resistantiscritical to improving patient survival. Evidence gathered in the
last decade suggests that tumor progression and recurrence may befuelled by
cancer stem cells (CSCs). Understanding how CSCs contribute to the pathology of
NPC will potentiallyaid the pursuit of novel therapies. In this review we
summarize what major methods are currently used to identify CSCs in NPC and the
Keywords: Nasopharyngeal carcinoma; Cancer stem cells
In general,two models have been proposed to explain tumor growth and
heterogeneity. In the first model, all tumor
cells are equipotent and a proportion of tumor cells stochastically proliferate
to fuel tumor growth while other tumor cells differentiate. In the second
model, tumors are hierarchically organized like normal tissues.Only a discrete
fraction of cells with stem cell features (asymmetric division) is able to
indefinitely sustain the malignant progeny through self-renewaland
differentiation processes. Owing to the analogy to tissue-specific stem cells , thesesubset of cells are called cancer
stem cells (CSCs) . Thetheory of the CSCshas stirred much confusion and debate ever
since, but it keeps generating excitement and optimism.
Almost 200 years ago, the father of pathology, Rudolf Virchow, suggested
that cancer cells arise from embryonic-like tissue, but it was not until 1994, in their pioneer work, have John Dick and
colleagues demonstrated the hierarchy of the acute myeloid leukaemia malignant
clone and defined the CSCs for the first time. Following these papers, many other studies have shown that
populations of cells presenting a higher ability to reform the parental tumor
on transplantation into immunodeficient mice can be prospectively isolated
from a great variety of solid tumors, such as breast cancer, brain tumors, colorectal cancer[7,8], skin squamous cell carcinoma
(SCC), head and neck cancer, lung cancer, pancreatic cancer, prostate cancer and ovarian cancer. Tumor cells
presenting this higher tumor-repopulating capacity have been referred to as
CSCs, or as tumor-initiating cells, but the best term to describe them is
probably tumor-propagating cells (TPCs).
Nasopharyngeal carcinoma (NPC) is a cancer arising from the epithelial
lining of the nasopharynx. It remains a serious health problem in many parts of
the world,although the worldwide incidence is low. NPC is particularly endemic
to regions in southern China and South East Asia [15,16].In Singapore, it ranks as the 3rdmost
common cancer in Chinese adult males between 35to 60 years old. Uniquely,
Epstein-Barr virus (EBV) is consistently detected in undifferentiated NPC from
these endemic regions.Particularly among
head and neck cancers of epithelial origin, it is associated with the highest
rateof locoregional recurrence and distant metastasis [18,19] , resulting in a
great interest in studying this disease with the intention of developing a
better understanding of its biology and translating these findings into improved
therapeutic approaches. One of the major mechanisms for recurrence of NPC has
been suggested by the CSCs proposition. While information on CSCs hasbeen
advanced in a variety of cancers, data in NPC is just emerging. In this paper,
we will review the evidence for CSCs in NPC and the future challenges ahead in
Discovery of NPC CSCs
Historically, the hematopoietic field has led the way in the
identification of stem cells and CSCs[4,21,22].The CSC-theory in solid tumors
was only validated relatively recently. Due to its distinctive racial/ethnic
and geographic distribution, studies of CSCs in NPC are very scarce[23,24,25,26,27,28,29,30,31] (Table 1). Several important
functional assays and surface markers have been used to investigate the
existence of cancer stem-like cells in various NPC cell lines. Overall, those
studies support the evidence of a subpopulation of NPC cells that are more
primitive, proliferative, therapy resistant and tumorigenic in xenograft than
cells with alternative phenotypes, suggesting CSCs.
Table 1 Markers for CSCs in NPC
% Cells expressing markers
EBV-NPC cell lines:SUNE-1(5-8F,
6-10B) and TMNE
approximately 0.3% of label-retaining cell (LRC) find
in 3 kinds of NPC xenografttumors
EBV- cell lines: CNE-2
2.6% of the total cells are SP cells
EBV- NPC cell line: SUNE-1( 5-8F)
CD44+ cells occupied 52.5% of the
EBV+ NPC cell line:C666-1
CD44+ cells accounted for 45.3% of
the total cells.
EBV+ NPC cell line C666-1 cells
C666-1 Spheroids Primary tumors
5.2861% of parental C666-1 cells are CD44+
84.1461% C666-1 spheroids are CD44+
13.06% of NPC xenografts are CD44+
Tissue sections from NPC patients
41 (39.0%) of 105 cases were defined as having
high-grade ALDH1 expression
EBV- NPC cell lines: 5-8F and CNE2
1.96% of cells are ALDH1 positive
8.5% with high ALDH activity
3.36±0.35% CD133+ cells
2.17% in primary cells
Label Retaining Cells (Lrcs)
Dye label–retaining technique can be used to identify normal tissues
that contain quiescent stem cells responsible for tissue homeostasis. As CSCs
can share properties with normal stem cells, slow-cycling cells might also
exist within a tumor. Their dormant state might account for the relapse in
cancer patients that can occur years to decades after apparently successful
treatment. In an early study by Zhang et al., the authors found there was about 0.3% of label retaining cells (LRC)
in NPC cell lines and their derived xenografttumors, a good indication that NPC
contains stem cells. However, what the lineage relationship of LRCs with the
rest of cells over time and their functions are lacking. This question could be
addressed further by isolation of live LRCs via fluorescence-activated cell
sorting(FACS)and applying them to functional assays[32,33,34].
Side Population (SP)
The side population (SP) discrimination assay is based on the
differential potential of cells to efflux the Hoechst dye via the ATP-binding cassette
(ABC) family of transporter proteins expressed within the cell membrane. SP
assay has proven to be a useful approach for the characterization and isolation
of putative stem cell and cancer stem cell populations, particularly in the
absence of specific markers. Wang et al. demonstrated ∼2.6% SP in CNE-2 line had cancer stem cell characteristics. These cells
were more resistant to chemotherapy and radiotherapy, and were noted to have
increased propensity to form tumors in vivo. The presence, absence or change in
SP has been used loosely as an indicator of CSC activity across cell lines in
some NPC drug testing studies [35,36,37]. However, whether SP is a robust CSC
marker in all NPC cells should beconfirmedsystematically. Studies in other
cancers even argue that SP is neither necessary nor sufficient for conferring a
CSC phenotype, such as glioblastomamultiforme (GBM), thyroid cancer,
gastrointestinal cancers and adrenocortical carcinoma.
Aldehyde Dehydrogenase (ALDH)
Another functional marker is aldehyde dehydrogenase 1 (ALDH1). ALDH1 is
normally responsible for maintaining cellular homeostasis by detoxifying
intracellular aldehydes through the oxidation and conversion of retinol to
retinoic acid. ALDH1 is highly expressed in hematopoietic stem cells, as well
as malignant CSCs[42,43,44]. It has been used as a
prognostic indicator of metastases and poor survival. Using EBVcell linesSUNE-1(5-8F) and CNE2,Wu et al. showed that ALDH1positive(1.96%) cells had faster proliferation,
higher clone formation, migration,tumor formation in mice, greaterstemness gene
expression and SP cells.It correlated with TNM staging and
epithelial-mesenchymal transition (EMT) makers, proposed as independent
prognostic indicators. Using EBV+cell line C666-1, our study demonstrated ALDHHigh (8.5%) cells possesscancer
stem-like traits: the cellsexhibited significantly greater ability to
proliferate, be clonogenic, resist chemotherapy drugs and radiation,
reconstitute a heterogeneous population,and express pluripotent markers.
Furthermore, subcutaneous injection of these cells into immunodeficient nude
mice resulted in a tendency of tumor formation at a higher rate (not
significant) as compared to cells with lowALDHactivity. However, we did not find
ALDHHigh cells are more migratory. Indeedwe showed almost all cells
express ALDH at variablelevels.There is no clear cut distinctionbetween
ALDH‘positive’ and ‘negative’ cells as Wu et al. termed it. The percentage is arbitrary and really depends on how
stringent one sets the gating. The discrepancy might be due to different
experimental conditions or the EBV status of the cell lines.Further research by
Luo et al. demonstrated that budding cells in the invasive front of tumors with
highlevel expression of ALDH1 correlated with aggressive tumor behaviour and
poor patient survival. The authors
speculated that they might possess the invasive and metastatic properties of
CSCs. Like in other cancers[46,47], ALDHcould be a potential therapeutic target for NPC CSCs as well.
CD44 is a cell surface receptor for the extracellular matrix molecule
hyaluronan. It influences cell behaviour by direct signaling/structural roles
or by acting as a co-receptor for receptor tyrosine kinases. CD44 alone or in combination with other markers have been used
successfully to enrich for CSCs in both cell line and tumor samples. Su et al.reported that CD44+
cells in SUNE-1(5-8F)weremore proliferative, enriched for stemness gene
expression and more resistant to therapy.But in vivo tumor imitation, one of
the most important criteria for CSCs,was not functionally addressed. In
contrast, Janisiewicz et al. demonstrated CD44+
C666-1 cells exhibited a more robust tumor-initiating capacity in the xenograft
model. CD44+ cells differentiated into CD44-
cells, indicating a hierarchical relationship. Patient tumors were
heterogeneous for CD44 staining, and a trend toward an association between CD44
expression and clinical outcome was observed. Surprisingly, no corresponding
higher proliferation rates were seen in CD44+ population in
vitro. This is consistent with our finding that no difference was detected for
both populations incolony-forming efficiency . This study raises the
question whether CD44- cells cannot survive in vivo or they
intrinsically cannot initiate tumors? In a more sophisticated study by
Lun et al., spheroid culture of C666-1 was
used to enrich for CSCs initially and they found the spheroid cells had at
least 50 times higher tumorigenic potential than the unselected cells. These
cells expressed significantlyhigher level of multiple stem cell markers (OCT4,
NANOG, ALDH1, CD44 and CD133 CKIT, KLF4 and KLF5). Further work on CD44 showed
that the majority of spheroids cells are CD44+ and the CD44+
cells were resistant to chemotherapeutic agents and with higher spheroid
formation efficiency and exhibited stronger chemo resistance to
fluorouracil5-FU.CD44+cells could give rise to both CD44+
and CD44- cells, suggesting a hierarchical relationship. The
phenotypic heterogeneity also was observed in xenografts and primary tumors.
Serial transplantation is an important measurement of long-term self-renewal
ability of CSCs. The authors reported spheroid cells could be serially
engrafted into nude mice, but no data has been shown in detail. Although
sphere-forming assays have been extensively used in many cancers to assess
clonogenicity, long-term renewal capacities and multiline age differentiation,
they must be interpreted with caution. It is important to note that not only
stem cells but also their transit-amplifying progeny are able to form spheres
and that, by contrast, quiescent stem cells cannot form spheres. Thus sphere
assays do not allow for an accurate quantification of stem cell frequency
in vivo. Even using the same protocol
for culturing C666-1 spheres, we were unable to form decent passageblespheres
from the primary NPC cells. Does it mean there are actually no CSCs in primary
NPC cells orit is just an artificial adaption for C666-1 line in long term in
vitro cultures? It will be important to define to what extent the ability
of tumor cells to grow as spheres is directly correlated with their ability to
sustain tumor growth in vivo.
CD133 (also known as Prominin 1), a member of pentaspan transmembrane
glycoproteins, is expressed in hematopoietic stem cells, endothelial progenitor
cells, neuronal and glial stem cells. It specifically localizes to cellular
protrusions. CD133 has previously also been
shown to be expressed in subpopulations of cancer cells from brain, colon,
lung, melanoma and other solid tumors. This led to the assumption that CD133
expressing tumor cells have stem cell or progenitor like properties and CD133
was proposed as CSC marker. Lun et al.found that 1.90±0.84% of CD133+in C666-1 cells
and completely absent in 2 of the
xenografts (xeno-666 and xeno-2117). Consistently, we only observed very rare
C666-1 cells with faint cytoplasmic but not surface staining of CD133.CD133 was
barely detectable in NPC primary cells or patient biopsies. However, Zhuang et al. reported
3.36±0.35%CD133+ cells with CSCs characteristics in
CNE cell lines. Overall their study is descriptive. For example, no significant
difference was formed in thecell cycle distribution between the CD133+
and CD133- cells, but CD133+ cells
hadsignificantlyhigher proliferative index and had a greater potential for in vivo
tumor formation. The CD133 expression dropped to zero at 21 days of culture.
Whether CD133 is a marker cannot be concluded from this study. Further
extensive studies with broader spectrum of cell lines, primary cells and
xenografts are needed.
Basically, the above studies have demonstrated that NPC cells are
heterogeneous and contain cancer stem-like cells. Based on these limited
publications, it is hard to say which marker works better than the other to
identify NPC CSCs. Even using the same cell line and same marker [26,27],
different results were obtained. The exact reasons for the reported
discrepancies across studies are not clear. Possible explanations may include
differences in techniques, protocols and reagents such as antibodies.
Additional sources of confusion may mirror the inter/intra-tumor heterogeneity
and colon evolution. These studies highlight the need for comprehensive
analysis by using combinations of different markers to identify potentially
unique functional characteristics of NPC CSCs. The gold standard of CSC
identification continues to be tumour initiation with serial transplantation in
recipient mice, but this may not be practical to NPC. It is very challenging
and will be discussed in the following section.
Despite the useful data we obtained from the above studies, there
are still many unsolved issues:
Where Do The NPC Cscs Come From?
The stem cell characteristics of CSCs beg the question of the cell type
from which they are derived. Experimental evidence suggests that CSCs arise
either from normal stem cells that have become cancerous through mutation, or
from the transformed somatic cells that have acquired the ability to
self-renew. Lineage tracing in experimental mouse models has strongly showed
that Lgr5+ intestinal stem cells can initiate and maintain murine
intestinal adenomas[52,53]. In mouse models of skin cancer, hair follicle bulge stem cells can serve as target cells for transformation, and CD34+
cells resembling their normal bulge stem cell counterpart are capable of
propagating the disease as a cancer stem cell population. In parallel, mouse models of breast cancer and recent studies using
human tumor samples demonstrate that tumors can arise and be propagated from
the transformation of more differentiated luminal cells.
In NPC, EBV infection is detected in nearly all patients in the endemic
regions.Although the underlying mechanism of how EBV contributes to cancer is
not completely understood, emerging data indicated that EBV latent membrane
protein LMP1 and LMP2a have transforming properties. Both proteins can activate
a number of signalling pathways such as NF-КB, STAT that trigger
morphological and phenotypic alterations in epithelial cells. Significantly,
they have been shown to induce EMT, increase the cancer stem cell-like population
and contribute to the onset of metastases in NPC[56,57,58].
A major question surrounding NPC is that it is not known whether or to
what extent epithelial cells become infected when the host first encounters EBV
during primary infection. One hypothesis isthat accumulation of genetic
alterations renders cells more permissive to latent EBV infection. High frequencies of chromosomal loss at 3p/9p are present in 80̴100% of NPC[60,61,62], which is similar to the level of EBV infection. This suggests that EBV
infection may not be the initiating event in NPC pathogenesis, but rather,
occurs before the initiation of invasive growth. Studies indicate that undifferentiated epithelial cells are more permissive
than the terminally differentiated cells for latent EBV infection and
Nasopharynx is lined by stratified squamous and respiratory type
epithelium. EBV infection of normal nasopharyngeal cells is rare. EBV-infected
epithelial cells are hardly detectable even in normal nasopharyngeal biopsies
from individuals who are at high risk of developing NPC. Basal cells in the epithelium of airway act as stem cells with
undifferentiated properties [65,66]. In addition to their role in epithelial homeostasis, basal cells
probably contribute to disease susceptibility, initiation and progression. For
example, disruption of the normal balance between proliferation and
differentiation in airway basal cells can leadto basal cell hyperplasia or
epithelial hypoplasia[66,67]. Similarly, recent studies demonstrated many cancers including
prostate cancer, skin basal cell carcinoma and basal-like breast cancer subtype
are originated in basal cells[68,69,70]. Consistently, we found almost
exclusively primary NPC cells are positive both for EBV and basal cell marker
p63(Figure 1). More importantly, like their normal counterpart, these
cells can be differentiated into goblet cells and ciliated cells(unpublished
data). The data suggest that basal stem cells could bethe initiating and
propagating cells of NPC,although we cannot rule out NPC initiating cells of
other origin such as transformed somatic cells.
Figure 1.Primary cell culture of nasopharyngeal carcinoma (NPC). Primary
NPC cells express EBV and basal cell markers revealed by immunohistochemistry with
antibodies against EBNA-1 and p63.
Are NPC Cscs Rare?
According to CSCs model, only a rare of population sits at the top of
the cellular hierarchy to drive the tumor progression. Indeed, in many types of
human tumors, CSCs have been shown to be rare, with frequencies ranging from
0.0001 to 0.1% determined by the capability of re‑forming secondary
tumors on transplantation into immunodeficient mice[71,72]. By contrast, Morrison and colleagues demonstrated that the transplantation of melanoma cells into more
severely immunodeficientNOD scid IL2 receptor gamma chain knockout mice (NSG)
mice enhances the frequency of CSCs by several orders of magnitude as compared
to nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Up to 27% of unselected melanoma cells from four
different patients were able to form xenografttumor, demonstrating that
CSCs are not always rare.Limiting-dilution transplants are typically used to
determine the frequency of CSCs. In available published NPC studies,nude mice
or NOD/SCID mice were frequently used(Table1).For example, in the study
by Lun et al. injection of at least 1,000 C666-1spheroid cells occasionally
formed one tumor out of six nude mice . In our own study , at least
10000 ALDHHighC666-1 cells were necessary for tumor formation in
nude mice.Couldthe frequency of NPC CSCs be underestimated? Almost all
NPC cells wereectopically transplanted into subcutaneous region, which does not
mimic the native environment and is suboptimal for engrafting[74,75]. This can be seen from the
experience ofxenografting either tissue explants or dissociated primary cells.
It is rarely a successful, even though a large number of cells were
transplanted.Orthotropic models[74,75] have been reported but it is not clear why it has not been extensively
used. On top of that, primary cells may be more accurate for localising CSCs
frequency within primary tumorsthan cell lines.Strikingly, we found more than
40% of primary NPC cells highly express CD44 andALDH (unpublished data). More
studies using primary cells and orthotropic modelsinmore severely
immunodeficient NSG mice are required to assess whether the lowfrequency of
CSCs found in NPC is the consequence of suboptimal assays rather than due to an
intrinsic inability to be propagated in immunodeficient mice.
Are NPC Cscsquiescent Or Fast Proliferating?
In many adult tissues[76,77,78], stem cells show a relative
slow turnover rate at homeostasis. For example, in the central nervous system, the
neural stem cells in the subventricular zone is a relatively quiescent
population with a cell cycle length up to 28 days, whereas the transit
amplifying progenitors cells (TA) divide rapidly with a cell cycle length of
approximately 12 h)[79,80].In melanoma, a subset of slow-cycling cells with
doubling times of >4 weeks within the rapidly proliferating main population
is essential for continuous tumor growth.However, in other adult tissues—such as the small
intestine—some cells with bona fide stem cell activity remain in an
actively dividing state.
Identification of CSCs has mostly been studied on the basis of
functional assays such as in vitro clonogenic assays, sphere formation and
tumorxenografting. It is important to note that all these assays are measuresof
proliferation. Do we deliberately select for fast proliferating cells? Are
these fast proliferating cells true CSCs or just TA progenitors?If the original
CSCs are quiescent in vivo but are stimulated to divide in cultures
containingserum and saturated growth factors), we might be able to capture the
cells. Conversely, if they do not respond to in vitro cultures (conditions are
not adequate), we might miss the CSCs.
Mathematical modelling of the clonal fate data suggest that the tumor is
hierarchically organized similarto normal epidermis, but CSCs divide rapidly
instead of being mostly quiescent (like stem cells) during normal homeostasis[83,84]. In contrast, Parada and
colleagues used a genetic lineage ablation
approach in a mouse model of glioblastoma to identify a subset of glioma CSCs
marked by Nestin. It found that these cells are responsible for
sustaining long-term tumor growth and relapse through the production of
transient populations of highly proliferative cells, but they themselves are
quiescent. Another study demonstrated that colon CSCs escape 5FU
chemotherapy-induced cell death by entering stemness and quiescence via the
c-Yes/YAP axis. As NPC is a disease which can
relapse(15%̴58%) and the
recurrent NPC is refectory to therapy, it is reasonable to think that there
might be some CSCs which are very quiescent and survive the primary radiation
and chemotherapy. To address this question, the development of NPC animal
models is necessary and lineage tracing will be helpful to assess the fate of
CSCs more directly within their natural environment.
Is NPC Cscs Status Stable Or Has Plasticity?
CSCs can divide asymmetrically to self-renew and generate differentiated
cells.This forms the basis of a unidirectional hierarchy of tumor. Like in most
studies using cell lines,CSCs are studied based on the assumption that it is a
defined subpopulation witha marker in a given cancer samples.This may over
simplify the complexity of the heterogeneity of in vivo tumors.Recent research
has identified unexpected plasticity of CSCs[81,88,89]. Chaffer et al. found that certain
degree of plasticity exist within a breast cell population, which allows
inter-conversion between CSC and non-CSC states when driven by selective pressures
(including therapy) or clonal evolution, indicating hierarchical models is not
unidirectional rather bidirectional, not stable rather dynamic. In intestinal
cells can give rise to LGR5+tumor cells, supporting the idea
that, when levels of active β‑catenin are increased, villus cells
can reacquire CSC properties by dedifferentiation.It has also been demonstrated that cell surface markers could be
dynamically and reversibly expressed by tumorigenic cells.In Wang’s studyit was found that Non-SP NPC cells can give rise to SP cells.We also found ALDHLowNPC cells can regenerate ALDHHighcells
, which suggest the possibility of plasticity instead of technical
limitation of FACS.Adding yet another layer of complexity is the notion that
there may exist more than one distinct cancer stem-like state within a
tumor,because CSCs keep accumulatingdriver and passenger
epigenetic and genetic perturbations during theirclone evolution andbranching[92,93]. As a result, phenotypic plasticity superimposes on a multiplicity of
pre-malignant and malignant subclones, which makes a single or universal maker
for CSCs seems impossible.
Understanding how NPC CSCs contribute to initiation and progression in
tumors will undoubtedly lead to the identification of novel targets. However,
the complexity of CSCs in terms of their heterogeneity and plasticity will make
any one single marker and drug unlikely to be efficient. An ideal strategy
would be to target boththe CSC andthe non-stem cells populations of tumor. More
importantly, the CSCs niche in which they are located is acritical determinant
of how they respond to a given treatment, which strongly put forward the niche as an important and
inseparabletarget for novel therapies[95,96,97].Signaling pathways that
potentially kill or differentiate CSCs have been increasingly identified, and
experimentally or clinically tested[92,98,99].
CSC study in NPC is still in its infancy. Using primary cells and
xenografts may be more disease relevant. Using orthotropic models in more
immunodeficent mice may be more accurate to investigate CSCs frequency.
Establishment of genetic lineage tracing models may allow more direct
trackingof CSCs in vivo. Therapies targeting NPC CSCs began to emerge [35,36,37,100]. We anticipate that in the near
future, successful targeting of CSCs will significantly improve outcomes in NPC
cancer patients and impact patient management.
Conflict of interest
The authors have no other funding, financial relationships, or conflicts
of interest to disclose.
Declaration of The Source of Funding
This work was supported by a Grant from the National University Cancer
Institute, Singapore (NCIS) Centre Grant to Dr.Loh andDr. Yu.
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