1

Review
Cancer Stem Cells in Nasopharyngeal Carcinoma: Current Evidence
Fenggang Yu1, Kwok Seng Loh2
1

Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Head & Neck Tumor Group, National Cancer Institute of Singapore, National University Health System (NUHS), Singapore

Corresponding author: Fenggang Yu; E-mail: entyf@nus.edu.sg

Citation: Yu FG, Loh KS. Cancer stem cells in nasopharyngeal carcinoma: current evidence. J Nasopharyng
Carcinoma, 2014, 1(6): e6. doi:10.15383/jnpc.6.
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 interests exist.
Conflict of interest: None.
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.

Abstract: Nasopharyngeal 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 challenges faced.
Keywords: Nasopharyngeal carcinoma; Cancer stem cells

Introduction

(CSCs) [2]. Thetheory of the CSCshas stirred much confusion

In general,two models have been proposed to explain tumor

and debate ever since, but it keeps generating excitement and

growth and heterogeneity[1]. In the first model, all tumor cells are

optimism.

equipotent and a proportion of tumor cells stochastically

Almost 200 years ago, the father of pathology, Rudolf Virchow,

proliferate to fuel tumor growth while other tumor cells

suggested that cancer cells arise from embryonic-like tissue[3],

differentiate. In the second model, tumors are hierarchically

but it was not until 1994, in their pioneer work, have John Dick

organized like normal tissues.Only a discrete fraction of cells with

and colleagues demonstrated the hierarchy of the acute myeloid

stem cell features (asymmetric division) is able to indefinitely

leukaemia malignant clone and defined the CSCs for the first

sustain

self-renewaland

time[4]. Following these papers, many other studies have shown

differentiation processes. Owing to the analogy to tissue-specific

that populations of cells presenting a higher ability to re-form the

stem cells , thesesubset of cells are called cancer stem cells

parental tumor on transplantation into immunodeficient mice can

JNPC http://www.journalofnasopharyngealcarcinoma.org/

e-ISSN 2312-0398

the

malignant

progeny

through

Published:2014-03 -20 DOI:10.15383/jnpc.6

be prospectively isolated from a great variety of solid tumors, such

better understanding of its biology and translating these findings

as breast cancer[5], brain tumors[6], colorectal cancer[7,8], skin

into improved therapeutic approaches. One of the major

squamous cell carcinoma (SCC)[9], head and neck cancer[10],

mechanisms for recurrence of NPC has been suggested by the

lung cancer[11], pancreatic cancer[12], prostate cancer[13] and

CSCs proposition[20]. While information on CSCs hasbeen

ovarian cancer[14]. Tumor cells presenting this higher tumor-

advanced in a variety of cancers, data in NPC is just emerging. In

repopulating capacity have been referred to as CSCs, or as tumor-

this paper, we will review the evidence for CSCs in NPC and the

initiating cells, but the best term to describe them is probably

future challenges ahead in elucidating this.

tumor-propagating cells (TPCs).

Nasopharyngeal carcinoma (NPC) is a cancer arising from the

Discovery of NPC CSCs

epithelial lining of the nasopharynx. It remains a serious health

Historically, the hematopoietic field has led the way in the

problem in many parts of the world,although the worldwide

identification of stem cells and CSCs[4,21,22].The CSC-theory in

incidence is low. NPC is particularly endemic to regions in

solid tumors was only validated relatively recently. Due to its

southern China and South East Asia [15,16].In Singapore, it ranks

distinctive racial/ethnic and geographic distribution, studies of

as the 3rdmost common cancer in Chinese adult males between

CSCs in NPC are very scarce[23,24,25,26,27,28,29,30,31] (Table

35to 60 years old. Uniquely, Epstein-Barr virus (EBV) is

1). Several important functional assays and surface markers have

consistently detected in undifferentiated NPC from these endemic

been used to investigate the existence of cancer stem-like cells in

regions[17].Particularly among head and neck cancers of epithelial

various NPC cell lines. Overall, those studies support the evidence

origin, it is associated with the highest rateof locoregional

of a subpopulation of NPC cells that are more primitive,

recurrence and distant metastasis [18,19] , resulting in a great

proliferative, therapy resistant and tumorigenic in xenograft than

interest in studying this disease with the intention of developing a

cells with alternative phenotypes, suggesting CSCs.

Table 1 Markers for CSCs in NPC

Marker

Samples

% Cells expressing markers

BrdU

EBV-NPC cell lines:SUNE- approximately 0.3% of label-retaining [23]

1(5-8F, 6-10B) and TMNE

Refs

cell (LRC) find in 3 kinds of NPC

xenografttumors

SP

EBV- cell lines: CNE-2

about

[24]

2.6% of the total cells are SP cells

EBV- NPC cell line: SUNE- CD44+ cells occupied 52.5% of the total

[25]

1( 5-8F)

cells

EBV+ NPC cell line:C666-1

CD44+ cells accounted for 45.3% of the [26]

CD44

total cells.
EBV+ NPC cell line C666-1 5.2861% of parental C666-1 cells are
cells

CD44+

And

84.1461% C666-1 spheroids are CD44+

C666-1 Spheroids

[27]

Primary 13.06% of NPC xenografts are CD44+

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Published:2014-03 -20 DOI:10.15383/jnpc.6

tumors
Xenografts
Tissue sections from NPC 41 (39.0%) of 105 cases were defined as [28]
patients
ALDH1

having high-grade ALDH1 expression

EBV- NPC cell lines: 5-8F 1.96% of cells are ALDH1 positive

[29]

and CNE2

CD133

C666-1

8.5% with high ALDH activity

[30]

CNE2

3.360.35% CD133+ cells

[31]

primary culture

2.17% in primary cells

Label Retaining Cells (Lrcs)

were more resistant to chemotherapy and radiotherapy, and were

Dye labelretaining technique can be used to identify normal

noted to have increased propensity to form tumors in vivo. The

tissues that contain quiescent stem cells responsible for tissue

presence, absence or change in SP has been used loosely as an

homeostasis. As CSCs can share properties with normal stem cells,

indicator of CSC activity across cell lines in some NPC drug

slow-cycling cells might also exist within a tumor. Their dormant

testing studies [35,36,37]. However, whether SP is a robust CSC

state might account for the relapse in cancer patients that can

marker in all NPC cells should beconfirmedsystematically. Studies

occur years to decades after apparently successful treatment. In an

in other cancers even argue that SP is neither necessary nor

early study by Zhang et al.[23], the authors found there was about

sufficient

0.3% of label retaining cells (LRC) in NPC cell lines and their

glioblastomamultiforme

derived xenografttumors, a good indication that NPC contains

gastrointestinal cancers[40] and adrenocortical carcinoma[41].

for

conferring

CSC

(GBM)[38],

phenotype,
thyroid

such

as

cancer[39],

stem cells. However, what the lineage relationship of LRCs with

the rest of cells over time and their functions are lacking. This

Aldehyde Dehydrogenase (ALDH)

question could be addressed further by isolation of live LRCs via

Another functional marker is aldehyde dehydrogenase 1 (ALDH1).

fluorescence-activated cell sorting(FACS)and applying them to

ALDH1 is normally responsible for maintaining cellular

functional assays[32,33,34].

homeostasis by detoxifying intracellular aldehydes through the

oxidation and conversion of retinol to retinoic acid. ALDH1 is

Side Population (SP)

highly expressed in hematopoietic stem cells, as well as malignant

The side population (SP) discrimination assay is based on the

CSCs[42,43,44]. It has been used as a prognostic indicator of

differential potential of cells to efflux the Hoechst dye via the

metastases and poor survival[45]. Using EBVcell linesSUNE-1(5-

ATP-binding cassette (ABC) family of transporter proteins

8F) and CNE2,Wu et al.[29] showed that ALDH1positive(1.96%)

expressed within the cell membrane. SP assay has proven to be a

cells

useful approach for the characterization and isolation of putative

migration,tumor

stem cell and cancer stem cell populations, particularly in the

expression and SP cells.It correlated with TNM staging and

absence of specific markers. Wang et al.[24] demonstrated 2.6%

epithelial-mesenchymal transition (EMT) makers, proposed as

SP in CNE-2 line had cancer stem cell characteristics. These cells

independent prognostic indicators. Using EBV+cell line C666-1,

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e-ISSN 2312-0398

had

faster

proliferation,

formation

in

higher

mice,

clone

formation,

greaterstemness

gene

Published:2014-03 -20 DOI:10.15383/jnpc.6

our study[30] demonstrated ALDHHigh (8.5%) cells possesscancer

clinical outcome was observed. Surprisingly, no corresponding

stem-like traits: the cellsexhibited significantly greater ability to

higher proliferation rates were seen in CD44+ population in vitro.

proliferate, be clonogenic, resist chemotherapy drugs and radiation,

This is consistent with our finding that no difference was detected

reconstitute a heterogeneous population,and express pluripotent

for both populations incolony-forming efficiency [30]. This study

markers. Furthermore, subcutaneous injection of these cells into

raises the question whether CD44- cells cannot survive in vivo or

immunodeficient nude mice resulted in a tendency of tumor

they intrinsically cannot initiate tumors? In a more sophisticated

formation at a higher rate (not significant) as compared to cells

study by Lun et al.[28], spheroid culture of C666-1 was used to

with lowALDHactivity. However, we did not find ALDHHigh cells

enrich for CSCs initially and they found the spheroid cells had at

are more migratory. Indeedwe showed almost all cells express

least 50 times higher tumorigenic potential than the unselected

ALDH at variablelevels.There is no clear cut distinctionbetween

cells. These cells expressed significantlyhigher level of multiple

ALDHpositive and negative cells as Wu et al.[29] termed it.

stem cell markers (OCT4, NANOG, ALDH1, CD44 and CD133

The percentage is arbitrary and really depends on how stringent

CKIT, KLF4 and KLF5). Further work on CD44 showed that the

one sets the gating. The discrepancy might be due to different

majority of spheroids cells are CD44+ and the CD44+ cells were

experimental conditions or the EBV status of the cell lines.Further

resistant to chemotherapeutic agents and with higher spheroid

research by Luo et al. demonstrated that budding cells in the

formation efficiency and exhibited stronger chemo resistance to

invasive front of tumors with highlevel expression of ALDH1

fluorouracil5-FU.CD44+cells could give rise to both CD44+ and

correlated with aggressive tumor behaviour and poor patient

CD44-

survival[28]. The authors speculated that they might possess the

phenotypic heterogeneity also was observed in xenografts and

invasive and metastatic properties of CSCs. Like in other

primary

cancers[46,47], ALDHcould be a potential therapeutic target for

measurement of long-term self-renewal ability of CSCs. The

NPC CSCs as well.

authors reported spheroid cells could be serially engrafted into

CD44

nude mice, but no data has been shown in detail.

CD44 is a cell surface receptor for the extracellular matrix

sphere-forming assays have been extensively used in many

molecule hyaluronan. It influences cell behaviour by direct

cancers to assess clonogenicity, long-term renewal capacities and

signaling/structural roles or by acting as a co-receptor for receptor

multiline age differentiation, they must be interpreted with caution.

tyrosine kinases[48]. CD44 alone or in combination with other

It is important to note that not only stem cells but also their transit-

markers have been used successfully to enrich for CSCs in both

amplifying progeny are able to form spheres and that, by contrast,

cell line and tumor samples[49]. Su et al.[25]reported that CD44+

quiescent stem cells cannot form spheres. Thus sphere assays do

cells in SUNE-1(5-8F)weremore proliferative, enriched for

not allow for an accurate quantification of stem cell frequency in

stemness gene expression and more resistant to therapy.But in

vivo[50]. Even using the same protocol for culturing C666-1

vivo tumor imitation, one of the most important criteria for

spheres, we were unable to form decent passageblespheres from

CSCs,was not functionally addressed. In contrast, Janisiewicz et

the primary NPC cells. Does it mean there are actually no CSCs in

al.[26] demonstrated CD44+ C666-1 cells exhibited a more robust

primary NPC cells orit is just an artificial adaption for C666-1 line

tumor-initiating capacity in the xenograft model. CD44+ cells

in long term in vitro cultures? It will be important to define to

differentiated into CD44- cells, indicating a

what extent the ability of tumor cells to grow as spheres is directly

hierarchical

cells,

suggesting

tumors.

Serial

hierarchical

transplantation

relationship.

is

an

The

important

Although

relationship. Patient tumors were heterogeneous for CD44 staining,

correlated with their ability to sustain tumor growth in vivo.

and a trend toward an association between CD44 expression and

CD133

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Published:2014-03 -20 DOI:10.15383/jnpc.6

CD133 (also known as Prominin 1), a member of pentaspan

be tumour initiation with serial transplantation in recipient mice,

transmembrane glycoproteins, is expressed in hematopoietic stem

but this may not be practical to NPC. It is very challenging and

cells, endothelial progenitor cells, neuronal and glial stem cells. It

will be discussed in the following section.

specifically localizes to cellular protrusions[51]. CD133 has

previously also been shown to be expressed in subpopulations of

Unsolved Issues

cancer cells from brain, colon, lung, melanoma and other solid

Despite the useful data we obtained from the above studies, there

tumors. This led to the assumption that CD133 expressing tumor

are still many unsolved issues:

cells have stem cell or progenitor like properties and CD133 was
proposed as CSC marker[51]. Lun et al.[27]found that

Where Do The NPC Cscs Come From?

1.900.84% of CD133+in C666-1 cells and completely absent in 2

The stem cell characteristics of CSCs beg the question of the cell

of the xenografts (xeno-666 and xeno-2117). Consistently, we

type from which they are derived. Experimental evidence suggests

only observed very rare C666-1 cells with faint cytoplasmic but

that CSCs arise either from normal stem cells that have become

not surface staining of CD133.CD133 was barely detectable in

cancerous through mutation, or from the transformed somatic cells

NPC primary cells or patient biopsies[30]. However, Zhuang et

that have acquired the ability to self-renew. Lineage tracing in

CSCs

experimental mouse models has strongly showed that Lgr5+

characteristics in CNE cell lines. Overall their study is descriptive.

intestinal stem cells can initiate and maintain murine intestinal

For example, no significant difference was formed in thecell cycle

adenomas[52,53]. In mouse models of skin cancer, hair follicle

distribution between the CD133+ and CD133- cells, but CD133+

bulge stem cells[54] can serve as target cells for transformation,

cells hadsignificantlyhigher proliferative index and had a greater

and CD34+ cells resembling their normal bulge stem cell

potential for in vivo tumor formation. The CD133 expression

counterpart are capable of propagating the disease as a cancer

dropped to zero at 21 days of culture. Whether CD133 is a marker

stem cell population[9]. In parallel, mouse models of breast cancer

cannot be concluded from this study. Further extensive studies

and recent studies using human tumor samples demonstrate that

with broader spectrum of cell lines, primary cells and

tumors can arise and be propagated from the transformation of

xenograftsareneeded.

more differentiated luminal cells[55].

Basically, the above studies have demonstrated that NPC cells are

In NPC, EBV infection is detected in nearly all patients in the

heterogeneous and contain cancer stem-like cells. Based on these

endemic regions.Although the underlying mechanism of how EBV

limited publications, it is hard to say which marker works better

contributes to cancer is not completely understood, emerging data

than the other to identify NPC CSCs. Even using the same cell

indicated that EBV latent membrane protein LMP1 and LMP2a

line and same marker [26,27], different results were obtained. The

have transforming properties. Both proteins can activate a number

exact reasons for the reported discrepancies across studies are not

of signalling pathways such as NF-B, STAT that trigger

clear. Possible explanations may include differences in techniques,

morphological and phenotypic alterations in epithelial cells.

protocols and reagents such as antibodies. Additional sources of

Significantly, they have been shown to induce EMT, increase the

confusion may mirror the inter/intra-tumor heterogeneity and

cancer stem cell-like population and contribute to the onset of

colon

metastases in NPC[56,57,58].

al.[31]

3.360.35%CD133+

reported

evolution.

These

studies

cells

highlight

with

the

need

for

comprehensive analysis by using combinations of different

A major question surrounding NPC is that it is not known whether

markers to identify potentially unique functional characteristics of

or to what extent epithelial cells become infected when the host

NPC CSCs. The gold standard of CSC identification continues to

first encounters EBV during primary infection. One hypothesis

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e-ISSN 2312-0398

Published:2014-03 -20 DOI:10.15383/jnpc.6

isthat accumulation of genetic alterations renders cells more

their role in epithelial homeostasis, basal cells probably contribute

permissive to latent EBV infection[59]. High frequencies of

to disease susceptibility, initiation and progression. For example,

80100% of

disruption of the normal balance between proliferation and

NPC[60,61,62], which is similar to the level of EBV infection.

differentiation in airway basal cells can leadto basal cell

This suggests that EBV infection may not be the initiating event in

hyperplasia or epithelial hypoplasia[66,67]. Similarly, recent

NPC pathogenesis, but rather, occurs before the initiation of

studies demonstrated many cancers including prostate cancer, skin

invasive growth. Studies[63] indicate that undifferentiated

basal cell carcinoma and basal-like breast cancer subtype are

epithelial cells are more permissive than the terminally

originated in basal cells[68,69,70]. Consistently, we found almost

differentiated cells for latent EBV infection and propagation.

exclusively primary NPC cells are positive both for EBV and

Nasopharynx is lined by stratified squamous and respiratory type

basal cell marker p63(Figure 1). More importantly, like their

epithelium. EBV infection of normal nasopharyngeal cells is rare.

normal counterpart, these cells can be differentiated into goblet

EBV-infected epithelial cells are hardly detectable even in normal

cells and ciliated cells(unpublished data). The data suggest that

nasopharyngeal biopsies from individuals who are at high risk of

basal stem cells could bethe initiating and propagating cells of

developing NPC[64]. Basal cells in the epithelium of airway act as

NPC,although we cannot rule out NPC initiating cells of other

stem cells with undifferentiated properties [65,66]. In addition to

origin such as transformed somatic cells.

chromosomal loss at

3p/9p are present in

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?

patients were able to form xenografttumor, demonstrating that

According to CSCs model, only a rare of population sits at the top

CSCs are not always rare.Limiting-dilution transplants are

of the cellular hierarchy to drive the tumor progression. Indeed, in

typically used to determine the frequency of CSCs. In available

many types of human tumors, CSCs have been shown to be rare,

published NPC studies,nude mice or NOD/SCID mice were

with frequencies ranging from 0.0001 to 0.1% determined by the

frequently used(Table1).For example, in the study by Lun et al.

capability of re-forming secondary tumors on transplantation into

injection of at least 1,000 C666-1spheroid cells occasionally

immunodeficient

and

formed one tumor out of six nude mice [27]. In our own study [30],

colleagues [73]demonstrated that the transplantation of melanoma

at least 10000 ALDHHighC666-1 cells were necessary for tumor

cells into more severely immunodeficientNOD scid IL2 receptor

formation in nude mice.Couldthe frequency of NPC CSCs be

gamma chain knockout mice (NSG) mice enhances the frequency

underestimated?

of CSCs by several orders of magnitude as compared to nonobese

transplanted into subcutaneous region, which does not mimic the

diabetic/severe combined immunodeficient (NOD/SCID) mice.

native environment and is suboptimal for engrafting[74,75]. This

Up to 27% of unselected melanoma cells from four different

can be seen from the experience ofxenografting either tissue

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e-ISSN 2312-0398

mice[71,72].

By

contrast,

Morrison

Almost

all

NPC

cells

wereectopically

Published:2014-03 -20 DOI:10.15383/jnpc.6

explants or dissociated primary cells. It is rarely a successful, even

CSCs divide rapidly instead of being mostly quiescent (like stem

though a large number of cells were transplanted.Orthotropic

cells) during normal homeostasis[83,84]. In contrast, Parada and

models[74,75] have been reported but it is not clear why it has not

colleagues[85] used a genetic lineage ablation approach in a

been extensively used. On top of that, primary cells may be more

mouse model of glioblastoma to identify a subset of glioma CSCs

accurate for localising CSCs frequency within primary tumorsthan

marked by Nestin. It found that these cells are responsible for

cell lines.Strikingly, we found more than 40% of primary NPC

sustaining long-term tumor growth and relapse through the

cells highly express CD44 andALDH (unpublished data). More

production of transient populations of highly proliferative cells,

studies using primary cells and orthotropic modelsinmore severely

but they themselves are quiescent. Another study demonstrated

immunodeficient NSG mice are required to assess whether the

that colon CSCs escape 5FU chemotherapy-induced cell death by

lowfrequency of CSCs found in NPC is the consequence of

entering stemness and quiescence via the c-Yes/YAP axis[86]. As

suboptimal assays rather than due to an intrinsic inability to be

NPC is a disease which can relapse

propagated in immunodeficient mice.

recurrent NPC is refectory to therapy, it is reasonable to think that

(15%58%) [87]and the

there might be some CSCs which are very quiescent and survive
Are NPC Cscsquiescent Or Fast Proliferating?

the primary radiation and chemotherapy. To address this question,

In many adult tissues[76,77,78], stem cells show a relative slow

the development of NPC animal models is necessary and lineage

turnover rate at homeostasis. For example, in the central nervous

tracing will be helpful to assess the fate of CSCs more directly

system, the neural stem cells in the subventricular zone is a

within their natural environment.

relatively quiescent population with a cell cycle length up to 28

days, whereas the transit amplifying progenitors cells (TA) divide

Is NPC Cscs Status Stable Or Has Plasticity?

rapidly with a cell cycle length of approximately 12 h)[79,80].In

CSCs can divide asymmetrically to self-renew and generate

melanoma, a subset of slow-cycling cells with doubling times

differentiated cells.This forms the basis of a unidirectional

of >4 weeks within the rapidly proliferating main population is

hierarchy of tumor. Like in most studies using cell lines,CSCs are

essential for continuous tumor growth[81].However, in other adult

studied based on the assumption that it is a defined subpopulation

tissuessuch as the small intestinesome cells with bona fide

witha marker in a given cancer samples.This may over simplify

stem cell activity remain in an actively dividing state[82].

the complexity of the heterogeneity of in vivo tumors.Recent

Identification of CSCs has mostly been studied on the basis of

research has identified unexpected plasticity of CSCs[81,88,89].

functional assays such as in vitro clonogenic assays, sphere

Chaffer et al.[89] found that certain degree of plasticity exist

formation and tumorxenografting. It is important to note that all

within a breast cell population, which allows inter-conversion

these assays are measuresof proliferation. Do we deliberately

between CSC and non-CSC states when driven by selective

select for fast proliferating cells? Are these fast proliferating cells

pressures (including therapy) or clonal evolution, indicating

true CSCs or just TA progenitors?If the original CSCs are

hierarchical models is not unidirectional rather bidirectional, not

quiescent in vivo but are stimulated to divide in cultures

stable rather dynamic. In intestinal tumors,LGR5- cells can give

containingserum and saturated growth factors), we might be able

rise to LGR5+tumor cells, supporting the idea that, when levels of

to capture the cells. Conversely, if they do not respond to in vitro

active -catenin are increased, villus cells can reacquire CSC

cultures (conditions are not adequate), we might miss the CSCs.

properties by dedifferentiation[90].It has also been demonstrated

Mathematical modelling of the clonal fate data suggest that the

that cell surface markers could be dynamically and reversibly

tumor is hierarchically organized similarto normal epidermis, but

expressed by tumorigenic cells[91].In Wangs study[24]it was

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e-ISSN 2312-0398

Published:2014-03 -20 DOI:10.15383/jnpc.6

found that Non-SP NPC cells can give rise to SP cells.We[30] also

The authors have no other funding, financial relationships, or

found ALDHLowNPC cells can regenerate ALDHHighcells , which

conflicts of interest to disclose.

suggest the possibility of plasticity instead of technical limitation

of FACS.Adding yet another layer of complexity is the notion that

Declaration of The Source of Funding

there may exist more than one distinct cancer stem-like state

This work was supported by a Grant from the National University

within a tumor,because CSCs keep accumulatingdriver and

Cancer Institute, Singapore (NCIS) Centre Grant to Dr.Loh andDr.

passenger epigenetic and genetic perturbations during theirclone

Yu.

evolution andbranching[92,93]. As a result, phenotypic plasticity

superimposes on a multiplicity of pre-malignant and malignant

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