Oral epithelial stem cells—Implications in normal development and cancer metastasis

doi:10.1016/j.yexcr.2014.04.021

Experimental Cell Research

Volume 325, Issue 2, 15 July 2014, Pages 111-129

https://doi.org/10.1016/j.yexcr.2014.04.021 Get rights and content

Highlights

•
Oral epithelium contains a reservoir of stem cells.
•
Stem cell markers have been localized mainly in the basal layer.
•
Cancer stem cells have been localized in head and neck tumors.
•
Cancer stem cells play a key role in oral cancer dissemination and metastasis.
•
Targeting oral cancer stem cells may improve disease outcome.

Abstract

Oral mucosa is continuously exposed to environmental forces and has to be constantly renewed. Accordingly, the oral mucosa epithelium contains a large reservoir of epithelial stem cells necessary for tissue homeostasis. Despite considerable scientific advances in stem cell behavior in a number of tissues, fewer studies have been devoted to the stem cells in the oral epithelium. Most of oral mucosa stem cells studies are focused on identifying cancer stem cells (CSC) in oral squamous cell carcinomas (OSCCs) among other head and neck cancers. OSCCs are the most prevalent epithelial tumors of the head and neck region, marked by their aggressiveness and invasiveness. Due to their highly tumorigenic properties, it has been suggested that CSC may be the critical population of cancer cells in the development of OSCC metastasis. This review presents a brief overview of epithelium stem cells with implications in oral health, and the clinical implications of the CSC concept in OSCC metastatic dissemination.

Introduction

Oral mucosa has a remarkable regenerative potential [1]. Several stem cells markers are known to be expressed, mainly in the basal layers of oral mucosa. It has been proven that the expression of these markers is dysregulated in oral squamous cell carcinomas (OSCC), the most common cancer of the oral cavity [2]. There is a need for a better characterization of the oral stem cells in particularly of their cell behavior, tissue-specific regenerative potential and involvement in carcinogenesis. This review provides an overview of stem cells biological implications in oral mucosa with a special emphasis in OSCC.

Section snippets

Oral mucosa

The epithelium on the inner surface of the lips, floor of the mouth, gingiva, cheeks and hard palate is derived from embryonic ectoderm, whereas the epithelium surrounding the tongue is derived from both endoderm and ectoderm [3], [4], [5]. The oral mucosa can be divided into: masticatory (hard palate and gingival), specialized (dorsal surface of the tongue) and lining (buccal mucosa, ventral surface of the tongue, soft palate, intra-oral surfaces of the lips and alveolar mucosa) [5]. Of the

Challenges to the integrity of the oral mucosa

The mucosal lining of the oral cavity is an environment challenged by a large variety of insults, and functions to protect the underlying tissues and organs against mechanical and chemical insults, including microorganisms and toxins, or ingested antigens and carcinogens [10]. The oral epithelium is constantly replaced with a rapid clearance of surface cells, which acts as a protective mechanism against various insults and its structure constitutes an effective barrier [10].

The turnover of the

Oral squamous cell carcinoma (OSCC)

OSCC is the most prevalent and aggressive epithelial tumor of the head and neck region with the poorest outcome; in the United States alone approximately 100 new cases are daily diagnosed, while one person dies from oral cancer every hour of every day [40], [41], [42], [43] (oralcancerfoundation.com). Worldwide, the problem is far greater with new cases annually exceeding 640,000 (oralcancerfoundation.com). Traditionally a men’s illness, affecting six men for every woman, over the past 10 years

Clinical relevance of cancer stem cells in oral tumorigenesis

The identification of cancer stem cells (CSC) has created a new area of research with promising applications in the prognosis and therapeutics of human cancer [68], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90]. Accumulating evidence indicates that the CSCs also play a role in the pathogenesis and progression of carcinomas developed in the oral cavity.

To date, two models of tumor heterogeneity are unanimously accepted: the hierarchical model that assumes

Implications of oral cancer stem cells in metastasis

Better purification of the stem-like cell population in oral carcinomas is necessary to clarify what metastatic characteristics are indeed unique to these cells. Such evidence would allow clinicians to exploit this particular set of attributes to target cancer stem cells that keep a tumor growing and allow it to spread. Our group has designed in vitro and in vivo models of metastasis to study the behavior of this unique tumor cell subpopulation in HNSCC. Our data showed that CSC possesses a

Therapeutic relevance of stem cells research

Primitive stem cells capable of self-renewing proliferation and single or multiple cell lineage progeny generation have been identified in several human epithelial tissues. Although the biological characterization of various non-hematopoietic stem cells is still in its early stages in the laboratory, therapeutic experience with hematopoietic stem cells suggests that other stem cell types will likely have successful clinical applications. Better understanding of pluripotentiality, control of

Disclosures

None.

Acknowledgments

This work was made possible by funding from the NCI NIDCR P50 CA 97248 (University of Michigan Head and Neck Cancer Specialized Program of Excellence in Research, SPORE) and the University of Michigan Undergraduate Research Opportunity Program (UROP). The funding sources had no involvement in the study design, data collection and analysis, and writing of this review.

References (225)

R. Iglesias-Bartolome et al.
Control of the epithelial stem cell epigenome: the shaping of epithelial stem cell identity
Curr. Opin. Cell Biol.
(2013)
N. Sinha et al.
Relevance of cancer initiating/stem cells in carcinogenesis and therapy resistance in oral cancer
Oral Oncol.
(2013)
T.A. Winning et al.
Oral mucosal embryology and histology
Clin. Dermatol.
(2000)
M. Rothova et al.
Lineage tracing of the endoderm during oral development
Dev. Dyn.
(2012)
K.B. Jones et al.
Oral epithelial stem cells in tissue maintenance and disease: the first steps in a long journey
Int. J. Oral Sci.
(2013)
L.M. Collins et al.
The surface area of the adult human mouth and thickness of the salivary film covering the teeth and oral mucosa
J. Dent. Res.
(1987)
L.V. Nguyen et al.
Cancer stem cells: an evolving concept
Nat. Rev. Cancer
(2012)
V. Richard et al.
The stem cell code in oral epithelial tumorigenesis: the cancer stem cell shift hypothesis
Biochim. Biophys. Acta
(2010)
A.A. Abdulmajeed et al.
Putative cancer stem cell marker expression in oral epithelial dysplasia and squamous cell carcinoma
J. Oral Pathol. Med. Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology
(2013)
C.A. Squier et al.
Biology of oral mucosa and esophagus
J. Nat. Cancer Inst. Monogr.
(2001)

C.A. Squier et al.

Human Oral Mucosa: Development, Structure and Function

(1976)

T. Wu et al.

Morphogenesis of rete ridges in human oral mucosa: a pioneering morphological and immunohistochemical study

Cell Tissues Organs

(2013)

R. Lanza, Essential of Stem Cell Bilogy. second ed. In: (Eds.) R. Lanza, J. Gearhart, B. Hogan, D. Melton, R. Pedersen,...

P.H. Jones et al.

Sic transit gloria: farewell to the epidermal transit amplifying cells?

Cell Stem Cell

(2007)

Y. Li et al.

Cancer stem cells: distinct entities or dynamically regulated phenotypes?

Cancer Res.

(2012)

G.A. Bjarnason et al.

Circadian variation in the expression of cell-cycle proteins in human oral epithelium

Am. J. Pathol.

(1999)

P.J. Thomson et al.

Mapping dynamic epithelial cell proliferative activity within the oral cavity of man: a new insight into carcinogenesis?

Br. J. Oral Maxillofacial Surg.

(1999)

W.J. Hume et al.

The ordered columnar structure of mouse filiform papillae

J. Cell Sci.

(1976)

W.J. Hume et al.

Proliferative units in startified squamous epithelium

Clin. Exp. Dermatol.

(1983)

M. Kellett et al.

A topographical study of the circadian rhythm in labelling index of mouse gingival and floor-of-mouth epithelium, including changes in labelling activity with individual cell position on the epithelial ridges

Arch. Oral Biol.

(1989)

P. Janich et al.

The circadian molecular clock creates epidermal stem cell heterogeneity

Nature

(2011)

L. Zheng et al.

Expression of clock proteins in developing tooth

Gene Expression Patterns: GEP

(2011)

M. Grimm et al.

Co-expression of CD44+/RANKL+ tumor cells in the carcinogenesis of oral squamous cell carcinoma

Odontology

(2013)

E.L. Abhold et al.

EGFR kinase promotes acquisition of stem cell-like properties: a potential therapeutic target in head and neck squamous cell carcinoma stem cells

PLoS One

(2012)

J. Du et al.

The nuclear localization of NFkappaB and p53 is positively correlated with HPV16 E7 level in laryngeal squamous cell carcinoma

J. Histochem. Cytochem.

(2003)

B.J. Nickoloff et al.

Notch signaling as a therapeutic target in cancer: a new approach to the development of cell fate modifying agents

Oncogene

(2003)

M. Al-Hajj et al.

Self-renewal and solid tumor stem cells

Oncogene

(2004)

S.S Karhadkar et al.

Hedgehog signalling in prostate regeneration, neoplasia and metastasis

Nature

(2004)

M. Dolled-Filhart et al.

Quantitative in situ analysis of beta-catenin expression in breast cancer shows decreased expression is associated with poor outcome

Cancer Res.

(2006)

A. Klaus et al.

signalling and its impact on development and cancer

Nat. Rev. Cancer

(2008)

K.M. Prise et al.

Concise review: stem cell effects in radiation risk

Stem Cells

(2011)

A.L. Carvalho et al.

Deleted in colorectal cancer is a putative conditional tumor-suppressor gene inactivated by promoter hypermethylation in head and neck squamous cell carcinoma

Cancer Res.

(2006)

H.K Tan et al.

Quantitative methylation analyses of resection margins predict local recurrences and disease-specific deaths in patients with head and neck squamous cell carcinomas

Br. J. Cancer

(2008)

W. Sun et al.

Detection of TIMP3 promoter hypermethylation in salivary rinse as an independent predictor of local recurrence-free survival in head and neck cancer

Clin. Cancer Res.

(2012)

J.A. Colacino et al.

Comprehensive analysis of DNA methylation in head and neck squamous cell carcinoma indicates differences by survival and clinicopathologic characteristics

PLoS One

(2013)

N. Agrawal et al.

Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1

Science

(2011)

N. Stransky et al.

The mutational landscape of head and neck squamous cell carcinoma

Science

(2011)

M.A. Sartor et al.

Genome-wide methylation and expression differences in HPV(+) and HPV(−) squamous cell carcinoma cell lines are consistent with divergent mechanisms of carcinogenesis

Epigenetics

(2011)

J.A. Colacino et al.

Pretreatment dietary intake is associated with tumor suppressor DNA methylation in head and neck squamous cell carcinomas

Epigenetics

(2012)

S.J. Arbes et al.

Factors contributing to the poorer survival of black Americans diagnosed with oral cancer (United States)

Cancer Causes Control

(1999)

A. Jemal et al.

Global cancer statistics

CA: Cancer J. Clin.

(2011)

M.T. Canto et al.

Oral cancer examinations among U.S. Hispanics in 1998

J. Cancer Educ.

(2003)

A.M. Horowitz et al.

Maryland adults’ knowledge of oral cancer and having oral cancer examinations

J. Public Health Dent.

(1998)

A.M. Eliassen et al.

Head and neck squamous cell carcinoma in pregnant women

Head Neck

(2013)

G.D. Cruz et al.

Oral cancer knowledge, risk factors and characteristics of subjects in a large oral cancer screening program

J. Am. Dent. Assoc.

(2002)

M. Hashibe et al.

Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the international head and neck cancer epidemiology consortium

Cancer Epidemiol. Biomarkers Prev.

(2009)

J. Ahn et al.

Oral microbiome and oral and gastrointestinal cancer risk

Cancer Causes Control

(2012)

H. Hausen

Infections Causing Human Cancer

(2006)

G. Pannone et al.

The role of human papillomavirus in the pathogenesis of head & neck squamous cell carcinoma: an overview

Infect. Agent Cancer

(2011)

L. Vidal et al.

Human papillomavirus in HNSCC: recognition of a distinct disease type

Hematol. Oncol. Clin. North Am.

(2008)

Cited by (41)

Molecular mechanisms underlying the epigallocatechin-3-gallate-mediated inhibition of oral squamous cell carcinogenesis
2023, Archives of Oral Biology
To reveal the mechanisms underlying the epigallocatechin-3-gallate (EGCG)-mediated inhibition of carcinogenesis and the related regulatory signaling pathways.
The effect of EGCG on the proliferation of OSCC cells was examined. SuperPred, ChEMBL, Swiss TargetPrediction, DisGeNET, GeneCards, and National Center for Biotechnology Information databases were used to predict the EGCG target genes and oral leukoplakia (OL)-related, oral submucosal fibrosis (OSF)-related, and OSCC-related genes. The binding of EGCG to the target proteins was simulated using AutoDock and PyMOL. The Cancer Genome Atlas (TCGA) dataset was subjected to consensus clustering analysis to predict the downstream molecules associated with these targets, as well as their potential functions and pathways.
EGCG significantly inhibited OSCC cell proliferation (p < 0.001). By comparing EGCG target genes with genes linked to oral potentially malignant disorder (OPMD) and OSCC, a total of eleven potential EGCG target genes were identified. Furthermore, EGCG has the capacity to bind to eleven proteins. Based on consensus clustering and enrichment analysis, it is suggested that EGCG may hinder the progression of cancer by altering the cell cycle and invasive properties in precancerous lesions of the oral cavity. Some possible strategies for modifying the cell cycle and invasive properties may include EGCG-mediated suppression of specific genes and proteins, which are associated with cancer development.
This study investigated the molecular mechanisms and signaling pathways associated with the EGCG-induced suppression of OSCC. The identification of specific pharmacological targets of EGCG during carcinogenesis is crucial for the development of innovative combination therapies involving EGCG.
Generation of hypothalamic neural stem cell-like cells in vitro from human pluripotent stem cells
2023, Stem Cell Reports
When damaged, restoring the function of the hypothalamus is currently impossible. It is unclear whether neural stem cells exist in the hypothalamus. Studies have reported that adult rodent tanycytes around the third ventricle function as hypothalamic neural stem cell-like cells. However, it is currently impossible to collect periventricular cells from humans. We attempted to generate hypothalamic neural stem cell-like cells from human embryonic stem cells (ESCs). We focused on retina and anterior neural fold homeobox (RAX) because its expression is gradually restricted to tanycytes during the late embryonic stage. We differentiated RAX::VENUS knockin human ESCs (hESCs) into hypothalamic organoids and sorted RAX⁺ cells from mature organoids. The isolated RAX⁺ cells formed neurospheres and exhibited self-renewal and multipotency. Neurogenesis was observed when neurospheres were transplanted into the mouse hypothalamus. We isolated RAX⁺ hypothalamic neural stem cell-like cells from wild-type human ES organoids. This is the first study to differentiate human hypothalamic neural stem cell-like cells from pluripotent stem cells.
Stereotactic Radiation Therapy for an Arteriovenous Malformation of the Oral Tongue: A Teaching Case
2022, Advances in Radiation Oncology
Citation Excerpt :
We additionally elected for an interval of 5 days between fractions with a goal of reducing acute toxicities by allowing time for oral mucosa repopulation, and because tumor repopulation was not a concern in a benign disease. The patient did have mucositis that developed approximately 3.5 weeks after treatment, consistent with turnover time of the oral mucosa.16 In the future, we would attempt to limit mucositis further with a longer bite piece to push the tongue away from the soft palate, which was not possible in the current case due to the shape of the patient's residual tongue.
Stereotactic radiotherapy is used with good efficacy for intracranial arteriovenous malformations, but experience in the head and neck region is limited.
A 21-year-old female presented with a high-flow arteriovenous malformation involving the bilateral anterior two-thirds of the oral tongue. She underwent near-total glossectomy, ligation of the bilateral lingual arteries and left facial artery, and reconstruction, which was followed by a large recurrence one year later. Angiography did not show an arterial source amenable to embolization, and the multidisciplinary team's recommendation was for stereotactic radiotherapy to the recurrent tongue arteriovenous malformation.
A custom oral fixation bite piece, in addition to a custom thermoplastic facemask and head sponge, were created. Simulation was performed using CT angiography. The arteriovenous malformation nidus was contoured, and an expansion of 2 mm was performed to determine the final planning target volume. The treatment plan consisted of five non-coplanar VMAT arcs. A total dose of 22 Gy given in two fractions spaced five days apart was prescribed. The patient developed grade 3 mucositis that peaked 3.5-5 weeks following treatment.
We describe the use of frameless stereotactic radiotherapy for a patient with a high-flow arteriovenous malformation of the oral tongue, including details of the procedure, novel techniques, and treatment planning considerations. Given the aggressive nature of head and neck arteriovenous malformations, the potentially serious functional limitations associated with extensive resections in the region, and the feasibility and tolerance of stereotactic radiotherapy, this technique should be considered for patients with head and neck AVMs and limited surgical or endovascular options.
Direct oral mucosal epithelial transplantation supplies stem cells and promotes corneal wound healing to treat refractory persistent corneal epithelial defects
2022, Experimental Eye Research
Persistent corneal epithelial defects (PED) can lead to irreversible blindness, seriously affecting the social function and life quality of these patients. When it comes to refractory PED, such as limbal stem cell deficiency (LSCD), that does not respond to standard managements, stem cell therapy is an ideal method. Oral mucosal epithelium (OME) abundant with stem cells within the base, is a promising autologous biomaterial, with much resemblance to corneal epithelial structures. In this experiment, uncultured autologous rat OME was directly applied to alkali burned corneas. Clinical evaluations and histological analyses showed that the transplantation accelerated the healing process, presenting faster re-epithelization and better formation of corneal epithelial barrier. To further investigate the therapeutic mechanism, oral epithelium was transplanted to de-epithelialized cornea in vitro for organ culture. It could be observed that the oral epithelial cells could migrate to the corneal surface and form smooth and stratified epithelium. Immunofluorescence staining results showed that the re-formed epithelium derived from OME, maintained stemness and transformed to corneal epithelial phenotype to some extent. Corneal stroma may provide the suitable microenvironment to promote the trans-differentiation of oral stem cells. Thus, both in vivo and in vitro experiments suggested that oral epithelium could play a positive role in treating refractory PED.
Title- Genomic landscape of squamous cell carcinoma- Different genetic pathways culminating in a common phenotype
2020, Cancer Treatment and Research Communications
Citation Excerpt :
Down regulation of NOTCH1 expression seems to be an inherent mechanism for reversal from a normal and mature to an activated and immature epithelium [40]. This pathway plays an important regulatory role in the oral, esophageal and bronchial epithelia [41-43]. Four family members are expressed in mammalian cells.
Squamous cell carcinomas (SqCCs) are the most common solid tumors in humans and are found across multiple organ systems. Although, integrated analysis of genetic alterations divulge similarities between SqCCs from various body sites, certain genes appear to be more frequently mutated in a given SqCC. These subtle differences may hold the key to determining the differentiation characteristics and predicting aggressiveness of tumors.
Fifty-four cases of SqCCs, in which the primary location of the tumor could be ascertained by clinical and radiological findings, were included in this study. Next generation sequencing data was analyzed for recurrent genetic abnormalities.
Genetic alterations were found in 219 genes in the 54 cases studied. TP53 mutations were found to be more frequent in pulmonary SqCCs (86.5%) as compared to non-pulmonary SqCCs (58.8%) (p<0.05). NOTCH gene family mutations and CREBBP mutations were limited to non-pulmonary SqCC (p<0.005) and were mutated in 41.2% and 17.6% cases.
A detailed comparative analysis of the genetic alterations identified by sequencing identified higher frequency of TP53 mutations in lung SqCCs as compared to non-pulmonary SqCCs. NOTCH and CREBPP mutations were found to be absent in lung and head and neck SqCCs and more frequent in SqCCs from other locations.
Heterogeneity within Stratified Epithelial Stem Cell Populations Maintains the Oral Mucosa in Response to Physiological Stress
2019, Cell Stem Cell
Stem cells in stratified epithelia are generally believed to adhere to a non-hierarchical single-progenitor model. Using lineage tracing and genetic label-retention assays, we show that the hard palatal epithelium of the oral cavity is unique in displaying marked proliferative heterogeneity. We identify a previously uncharacterized, infrequently-dividing stem cell population that resides within a candidate niche, the junctional zone (JZ). JZ stem cells tend to self-renew by planar symmetric divisions, respond to masticatory stresses, and promote wound healing, whereas frequently-dividing cells reside outside the JZ, preferentially renew through perpendicular asymmetric divisions, and are less responsive to injury. LRIG1 is enriched in the infrequently-dividing population in homeostasis, dynamically changes expression in response to tissue stresses, and promotes quiescence, whereas Igfbp5 preferentially labels a rapidly-growing, differentiation-prone population. These studies establish the oral mucosa as an important model system to study epithelial stem cell populations and how they respond to tissue stresses.

View all citing articles on Scopus

View full text

Review ArticleOral epithelial stem cells—Implications in normal development and cancer metastasis

Highlights

Abstract

Introduction

Section snippets

Oral mucosa

Challenges to the integrity of the oral mucosa

Oral squamous cell carcinoma (OSCC)

Clinical relevance of cancer stem cells in oral tumorigenesis

Implications of oral cancer stem cells in metastasis

Therapeutic relevance of stem cells research

Disclosures

Acknowledgments

Control of the epithelial stem cell epigenome: the shaping of epithelial stem cell identity

Curr. Opin. Cell Biol.

Relevance of cancer initiating/stem cells in carcinogenesis and therapy resistance in oral cancer

Oral Oncol.

Oral mucosal embryology and histology

Clin. Dermatol.

Lineage tracing of the endoderm during oral development

Dev. Dyn.

Oral epithelial stem cells in tissue maintenance and disease: the first steps in a long journey

Int. J. Oral Sci.

The surface area of the adult human mouth and thickness of the salivary film covering the teeth and oral mucosa

J. Dent. Res.

Cancer stem cells: an evolving concept

Nat. Rev. Cancer

The stem cell code in oral epithelial tumorigenesis: the cancer stem cell shift hypothesis

Biochim. Biophys. Acta

Putative cancer stem cell marker expression in oral epithelial dysplasia and squamous cell carcinoma

J. Oral Pathol. Med. Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology

Biology of oral mucosa and esophagus

J. Nat. Cancer Inst. Monogr.

Human Oral Mucosa: Development, Structure and Function

Morphogenesis of rete ridges in human oral mucosa: a pioneering morphological and immunohistochemical study

Cell Tissues Organs

Sic transit gloria: farewell to the epidermal transit amplifying cells?

Cell Stem Cell

Cancer stem cells: distinct entities or dynamically regulated phenotypes?

Cancer Res.

Circadian variation in the expression of cell-cycle proteins in human oral epithelium

Am. J. Pathol.

Mapping dynamic epithelial cell proliferative activity within the oral cavity of man: a new insight into carcinogenesis?

Br. J. Oral Maxillofacial Surg.

The ordered columnar structure of mouse filiform papillae

J. Cell Sci.

Proliferative units in startified squamous epithelium

Clin. Exp. Dermatol.

A topographical study of the circadian rhythm in labelling index of mouse gingival and floor-of-mouth epithelium, including changes in labelling activity with individual cell position on the epithelial ridges

Arch. Oral Biol.

The circadian molecular clock creates epidermal stem cell heterogeneity

Nature

Expression of clock proteins in developing tooth

Gene Expression Patterns: GEP

Co-expression of CD44+/RANKL+ tumor cells in the carcinogenesis of oral squamous cell carcinoma

Odontology

EGFR kinase promotes acquisition of stem cell-like properties: a potential therapeutic target in head and neck squamous cell carcinoma stem cells

PLoS One

The nuclear localization of NFkappaB and p53 is positively correlated with HPV16 E7 level in laryngeal squamous cell carcinoma

J. Histochem. Cytochem.

Notch signaling as a therapeutic target in cancer: a new approach to the development of cell fate modifying agents

Oncogene

Self-renewal and solid tumor stem cells

Oncogene

Hedgehog signalling in prostate regeneration, neoplasia and metastasis

Nature

Quantitative in situ analysis of beta-catenin expression in breast cancer shows decreased expression is associated with poor outcome

Cancer Res.

signalling and its impact on development and cancer

Nat. Rev. Cancer

Concise review: stem cell effects in radiation risk

Stem Cells

Deleted in colorectal cancer is a putative conditional tumor-suppressor gene inactivated by promoter hypermethylation in head and neck squamous cell carcinoma

Cancer Res.

Quantitative methylation analyses of resection margins predict local recurrences and disease-specific deaths in patients with head and neck squamous cell carcinomas

Br. J. Cancer

Detection of TIMP3 promoter hypermethylation in salivary rinse as an independent predictor of local recurrence-free survival in head and neck cancer

Clin. Cancer Res.

Comprehensive analysis of DNA methylation in head and neck squamous cell carcinoma indicates differences by survival and clinicopathologic characteristics

PLoS One

Review Article
Oral epithelial stem cells—Implications in normal development and cancer metastasis