Year : 2010 | Volume
: 6 | Issue : 4 | Page : 411--413
Cancer stem cells: An enigma in head and neck cancer
Rehan Kazi1, Suhail I Sayed2, Raghav C Dwivedi1,
1 Head and Neck Unit, Royal Marsden Hospital, London SW3 6JJ, United Kingdom
2 Department of ENT, Grant Medical College, B.R. Ambedkar Road, Byculla, Mumbai - 8, India
Head and Neck Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ
|How to cite this article:|
Kazi R, Sayed SI, Dwivedi RC. Cancer stem cells: An enigma in head and neck cancer.J Can Res Ther 2010;6:411-413
|How to cite this URL:|
Kazi R, Sayed SI, Dwivedi RC. Cancer stem cells: An enigma in head and neck cancer. J Can Res Ther [serial online] 2010 [cited 2020 Jan 25 ];6:411-413
Available from: http://www.cancerjournal.net/text.asp?2010/6/4/411/77061
Head and neck squamous cell cancer (HNSCC) is the sixth most common cancer in the world.  Effective therapeutic modalities such as surgery, radiation, chemotherapy and/or combinations are used in the management of this disease. Efforts are ongoing throughout the world to improve early detection and prevention of HNSCCs. To date, there still lingers the daunting challenge of the identification of the cell type implicated in the initiation and sustaining growth of the tumor. Evidence is accumulating to show that tumor growth and propagation is often dependent on a rare subset of cells (<1% of the total tumor cell population) known as "cancer stem cells" (CSCs). The term "cancer stem cells" is defined by the American Association for Cancer Research Workshop on Cancer Stem Cells as a cell within a tumor that possesses the capacity to self-renew and to generate heterogeneous lineages of cancer cells that comprise the tumor.  CSCs were first isolated by Bonnet and Dijk (1997) in acute myeloid leukemia, whereas Al Hajj (2003) was the first to identify them in solid tumors. , Identification of these biologically distinct cells has ushered in new insights in understanding the phenomenon of tumor initiation and progression, providing hope for effective therapeutic modalities in our pursuit for giving a cure for this dreaded disease.
The CSC terminology is based on the concept that like normal stem cells of the body, these cells possess the capacity for self-renewal and differentiate into mature, but "aberrant", progeny. CSCs possess the following potentials which render them "immortal": self-renewal capacity, high migratory ability, high proliferation capacity and drug resistance. Although carcinogenesis has been explained in the past by the "stochastic model" which propounds a cellular origin of tumors in that every cancer cell has the ability to be the founder of a new tumor, it has only been recently explained based on the "CSC model" which proposes that cancer evolution occurs from tissue progenitor or stem cells which have a "deregulated" self-renewal pathway. , The signaling pathways which are involved in these mechanisms are the Wnt, Hedgehog, Notch and Oct-4. These signals arise from the CSC "niche" and their derangement can lead to the deregulation in the self-renewal of stem cells, leading to carcinogenesis. , CSCs grow in a "niche" which protects them from the exogenous agents and this environment has also been implicated to protect the cells from the effects of radiation by hypoxia. 
The identification and characterization of the CSCs by means of specific molecular markers can guide us in developing efficacious targeted therapies and prevent tumor recurrences.  To some extent, with the help of diagnostic techniques like dual wavelength flow cytometry, it has been possible to detect molecular markers in solid HNSCC. The most commonly used cell markers to date have been CD34, CD133, CD24, CD44, CD29 and CD31.  CD44+ CSCs have been implicated in the phenomenon of tumor progression and metastasis.  Also, CD44+ cells in the tumor population express high levels of nuclear BMI-1.  BMI-1 is a stem cell related gene implicated in carcinogenesis of leukemia, lymphomas, lung and breast cancer.  The combined evaluation of both CD44 and BMI-1 can lead to precise evaluation and characterization of the CSC population in the tumor cellular architecture. Only recently, aldehyde dehydrogenase 1 (ALDH1) has been propounded as a marker for HNC with the ALDH1 + cells exhibiting high self-renewal capacity and radioresistance.  While on one hand these molecular markers can lead to an early identification of the CSC tumor population, on the other hand they can also predict the tumor behavior, aggressiveness and suggest the prognosis (e.g. ALDH1 + cells are considered to be more aggressive and develop metastasis). Early detection of the CSCs will have an effective bearing and can definitely alter the current treatment protocols. Also, a cognition of the pathways involved in the CSC differentiation which ultimately lead to CSC "immortality" holds importance as these are the likely targets for developing therapeutic models which can prevent these cells from undergoing genomic instability and alteration at an earliest stage in tumorigenesis. Although the molecular markers of CSCs can provide useful information with respect to tumor pathogenicity, it is still not clear whether every marker-positive cell has the property of being a CSC. 
CSCs also have been implicated recently in tumor vasculogenesis. But these are preliminary results and further research is required to prove these facts in order to devise suitable therapeutic modalities. Study of the molecular mechanisms which transform normal stem cells to CSCs is warranted in order to develop strategies to prevent this phenomenon.  The current scenario of the anti-angiogenic chemotherapeutic drugs' failure to show efficacious results in tumor control rates may lie in their capability to affect the CSC population. 
CSCs are derived from normal stem cells of the body, which have a pivotal role in an individual's organogenesis. These cells need to be resilient in nature so that they continue the ongoing process of cellular turnover for an individual, providing them with a regular supply of newly differentiated cells for tissue maintenance and repair. This ongoing process is a result of molecular pathways which protect the CSCs from the process of apoptosis, i.e. programmed cell death, and paradoxically render them inert to the apoptosis induced by the cytotoxic drugs and radiation therapy. This answers the phenomenon of tumor recurrences seen in patients thought to have been adequately treated for their disease. CSCs and normal stem cells of the body share common molecular pathways, and therapies designed to combat CSCs can also affect the normal cells, leading to toxicities. Hence, there is a need to develop targeted therapies specific for the CSCs.
There exists a lacuna in the study of CSCs due to their meager number in the tumor cell population. To add to this is the major limitation of obtaining an adequate tissue specimen from the head and neck region without compromising the patient's quality of life. To date, there have been no successful documented in-vitro/in-vivo culture studies for HNSCC cell lines. Hence, there is a need for developing robust in vitro and in vivo study models to evaluate the CSCs' molecular biology. The employment of nude (immunocompromised) mice for tumor expansion holds promise. Also, there is evidence to support this modality as it has been found that this method does not significantly alter the cancer cell phenotype. Further, there are still no accurate data signifying the origin of CSCs, and hence, there exists a need to evaluate the mutations occurring over a period of time which lead to the transformation of normal stem cells to CSCs. CSCs still prove to be an enigma in our quest to find an answer to the phenomenon of tumor initiation, progression and recurrences. Also, this cell population holds the key for providing cure for this dreaded disease. CSC should be considered as an additional tumor type and therapeutic modalities should be explored catering to this enigmatic cell population.
Current research has focused on evaluation of the transcription factors, viz., Snail, Slug, Twist, and SIP, in CSC evolution. The upregulation of these transcription factors has been demonstrated in the pathogenesis of HNSCCs. , While the major impetus in isolating CSCs has been for the identification of CSC-specific surface markers, it is prudent to identify the specific CSC associated genes from tumor expression profiles as biomarkers and evaluate their correlation with patient survival, i.e., functional evaluation. This methodology will definitely improve the sensitivity and specificity of the prognostic/predictive value of these CSC biomarkers.
The current research has provided us a useful insight in understanding the role of CSCs in evolution of head and neck cancers. But still, there exists caveats in understanding the exact origins and mechanisms of survival of this enigmatic cell population. CSC research should be carried out in the near future with an aim to evaluate the existence, association and contribution of these cells to the tumor biology and pathogenesis. This effort may ultimately make the promise of specifically targeting these cells in cancer therapeutics a reality.
|1||Ferlay F, Pisani BP, Parkin DM. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide IARC CancerBase No. 5. version 2.0, Lyon: IARC Press; 2004. Available from: http://www-dep.iarc.fr/ [last cited on 2004].|
|2||Clarke MF , Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, et al. Cancer stem cells: Perspectives on current status and future directions: AACR Workshop on Cancer Stem Cells. Cancer Res 2006;66:9339-44.|
|3||Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3:730-7.|
|4||Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 2003;100:3983-8.|
|5||Morrison SJ, Spradling AC. Stem cells and niches: Mechanisms that promote stem cell maintenance throughout life. Cell 2008;132:598-611.|
|6||Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS. Role of Notch signaling in cell-fate determination of human mammary stem/ progenitor cells. Breast Cancer Res 2004;6:R605-15.|
|7||Olsen CL, Hsu PP, Glienke J, Rubanyi GM, Brooks AR. Hedgehog-interacting protein is highly expressed in endothelial cells but down-regulated during angiogenesis and in several human tumor. BMC Cancer 2004;4:43. |
|8||Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA 2007;104:973-8.|
|9||Mackenzie IC. Stem cell properties and epithelial malignancies. Eur J Cancer 2006;42:1204-12. |
|10||Hill RP, Perris R. "Destemming" cancer stem cells. J Natl Cancer Inst 2007;99:1435-40. |
|11||Chen YC, Chen YW, Hsu HS, Tseng LM, Huang PI, Lu KH, et al. Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer. Biochem Biophys Res Commun 2009;385:307-13. |
|12||Mack B, Gires O. CD44s and CD44v6 expression in head and neck epithelia. PLoS One 2008;3:e3360. |
|13||Chen L, Shen R, Ye Y, Pu XA, Liu X, Duan W, et al. Precancerous stem cells have the potential for both benign and malignant differentiation. PLoS One 2007;2:e293.|
|14||Medina MA, Munoz-Ch Puli R, Quesada AR. Challenges of antiangiogenic cancer therapy: Trials and errors, and renewed hope. J Cell Mol Med 2007;11:374-82. |
|15||Moreno-Bueno G, Cubillo G, Sarrió D, Peinado H, Rodríguez-Pinilla SM, Villa S, et al. Genetic profiling of epithelial cells expressing E-cadherin repressors reveals a distinct role for Snail, Slug, and E47 factors in epithelial-mesenchymal transition. Cancer Res 2006;66:9543-56.|
|16||Hsu DS, Lan HY, Huang CH, Tai SK, Chang SY, Tsai TL, et al. Regulation of excision repair cross-complementation group 1 by Snail contributes to cisplatin resistance in head and neck cancer. Clin Cancer Res 2010;16:4561-71.|