Cancer Stem Cells in Nasopharyngeal Carcinoma: Current Evidence

Fenggang Yu1, Kwok Seng Loh2


1Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

2Head & 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: http://journalofnasopharyngealcarcinoma.org/Resource/image/20140307/20140307234733_0340.png2014 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




In general,two models have been proposed to explain tumor growth and heterogeneity[1]. 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) [2]. 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[3], 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[4]. 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[5], brain tumors[6], colorectal cancer[7,8], skin squamous cell carcinoma (SCC)[9], head and neck cancer[10], lung cancer[11], pancreatic cancer[12], prostate cancer[13] and ovarian can­cer[14]. 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[17].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[20]. 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 elucidating this.


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 total



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




 primary culture

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.[23], 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.[24] 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)[38], thyroid cancer[39], gastrointestinal cancers[40] and adrenocortical carcinoma[41].


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[45]. Using EBVcell linesSUNE-1(5-8F) and CNE2,Wu et al.[29] 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[30] 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.[29] 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[28]. 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[48]. CD44 alone or in combination with other markers have been used successfully to enrich for CSCs in both cell line and tumor samples[49]. Su et al.[25]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.[26] 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 [30]. 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.[28], 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[50]. 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[51]. 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[51]. Lun et al.[27]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[30]. However, Zhuang et al.[31] 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.


Unsolved Issues

 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[54] 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[9]. 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[55].

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[59]. 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[63] indicate that undifferentiated epithelial cells are more permissive than the terminally differentiated cells for latent EBV infection and propagation.

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[64]. 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 [73]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 [27]. In our own study [30], 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[81].However, in other adult tissues—such as the small intestine—some cells with bona fide stem cell activity remain in an actively dividing state[82].

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[85] 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[86]. As NPC is a disease which can relapse(15%̴58%) [87]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.[89] 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 tumors,LGR5 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[90].It has also been demonstrated that cell surface markers could be dynamically and reversibly expressed by tumorigenic cells[91].In Wang’s study[24]it was found that Non-SP NPC cells can give rise to SP cells.We[30] 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[94], 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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