Unraveling the role of epidermal growth factor receptor in oral lesions: Key to non surgical treatment modes Bhavna Chulliparampil Mohan, Punnya Vaijanath Angadi
Mohan BC, Angadi PV. Unraveling the role of epidermal growth factor receptor in oral lesions: Key to non surgical treatment modes. World J Stomatol 2015; 4(1): 22-28
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
This review addresses the importance and need to understand epidermal growth factor receptor (EGFR) related pathogenesis in oral lesions and the possible effectiveness of anti-EGFR agents in treating these conditions.
Order reprints or request permissions: firstname.lastname@example.org
NAME OF JOURNAL
World Journal of Stomatology
2218-6263 ( online)
Published by Baishideng Publishing Group Inc, 8226 Regency Drive, Pleasanton, CA 94588, USA
ESPS Manuscript NO: 12367
Unraveling the role of epidermal growth factor receptor in oral lesions: Key to non surgical treatment modes Bhavna Chulliparampil Mohan, Punnya Vaijanath Angadi
Bhavna Chulliparampil Mohan, Department of Oral Pathology and Medicine, Annoor Dental College, Muvattupuzha, Kerala 686673, India
Punnya Vaijanath Angadi, Department of Oral Pathology and Microbiology, KLEVK Institute of Dental Sciences and Hospital, Belgaum 590010, Karnataka, India
Author contributions: Mohan BC and Angadi PV contributed equally to this work, generated figures and wrote the manuscript.
Conflict-of-interest: The authors declare that there is no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accor dance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Punnya Vaijanath Angadi, Reader, Department of Oral Pathology and Microbiology, KLEVK Institute of Dental Sciences and Hospital, Nehrunagar, Belgaum 590010, Karnataka, India. email@example.com
Received: July 4, 2014
Peer-review started: July 6, 2014
First decision: September 16, 2014
Revised: December 11, 2014
Accepted: December 29, 2014
Article in press: December 31, 2014
Published online: February 20, 2015
Epidermal growth factor receptor (EGFR) is a transmembrane receptor with tyrosine kinase activity, mediating actions of various growth factors including EGF, transforming growth factor-α, and neuregulins. Protein binding to ligand induces receptor modification, tyrosine autophosphorylation leading to cell signaling resulting in cellular proliferation. This receptor plays diverse roles in maintaining homeostasis and recent molecular advances identify that EGFR mutations are linked to several carcinomas. EGFR plays important roles in the development and maintenance of various oral structures, tooth development, eruption and morphogenesis. EGFR expression has also been studied in diverse oral pathologies like squamous cell carcinomas, potentially malignant lesions, lichen planus, salivary gland tumors and odontogenic cysts and tumours. The present review delves into the various general features of EGFR with an insight into its physiological and pathological role in the oral cavity. The clinical implications and upcoming role of EGFR inhibitors in the nonsurgical treatment of oral lesions has also been discussed.
The epidermal growth factor receptor (EGFR) is nowadays being studied because of the possible role of using EGFR inhibitors in the cancer chemotherapy. EGFR is the prototypal member of four homologous transmembrane proteins and was the first protein in this family to have been sequenced and identified to have tyrosine kinase activity[2-5]. EGFR is also referred to as HER (human EGF receptor) and c-erbB1and is encoded by the EGFR gene located on chromosome 7p12. This transmembrane glycoprotein comprises of 1186 amino acids having three main parts; extracellular domain (ECD), transmembrane pass (TM) and intracellular domain (ICD) (Figure 1).
In vertebrates, among the four EGFR family members (ErbB1, ErbB2, ErbB3 and ErbB4), overall similarity among the amino acids is about 50%. The receptors EGFR family are together create an interacting system that receives and processes information that results in multiple cellular functions. EGFR binds to EGF, amphiregulin and TGF-α and ligands like betacellulin, heparin-binding EGF and epiregulin bind to the EGFR as well as ErbB4. The ErbB2/HER2/neu does not bind ligands and ErbB3/HER3 has an inactive kinase domain, and these receptors are thought to serve as co-receptors. Neuregulins 1 (NGR1) and Neuregulins 2 (NGR2) bind preferentially to ErbB3 and ErbB4 and the ligands NGR3 and NGR4 bind to ErbB4 (Figure 2). Ligand bonding initiates shape alteration that unmasks a “dimerization loop,” thereby triggering receptor homo-dimerization or hetero-dimerization which causes tyrosine trans-phosphorylation leading to activation of downstream signaling cascades. These pathways are often functionally interlinked and ideally should not be considered in isolation; however, for the sake of simplicity most authors discuss them individually[7-10].
The EGFR family is a diverse signaler and plays important physiological roles in determining cell lineage, organ morphogenesis, cell adaptation, motility, proliferation and apoptosis[5,7]. Damjanov et al in 1986 conducted a study to identify EGFR in various tissues in human oral mucosa and suggested that membrane EGFR location depicts a more responsive cell than cytoplasmic EGFR localization This study said that it is likely that differential distribution of the EGFR to specific cell types and cellular compartments may signify adaptations that permit growth factor responsiveness in the surroundings of available ligand. EGFR also interacts with RANK resulting in RANKL signaling pathways which helps in osteoclast differentiation and survival.
In general pathology EGFR plays a major role in human cancers. Aberrant EGFR signaling are initiated by several events, such as altered ligand production, receptor mutations or deletions and continuous signaling leading to uncontrolled cell multiplication, invasion, increased angiogenesis and metastasis[7,13-15]. EGFR also plays an important role in stopping autophagic cell death induced by death receptors which is one of the mechanisms that initiate cancer.Another recent EGFR mechanism that was identified is the tyrosine kinase independent mode in which EGFR prevents cancer cells from apoptosis by regulating the basal intracellular glucose level via the sodium/glucose co transporter 1. EGFR has varied effects in the prognosis of various cancers. This is speculated to be an important reason for the aggressiveness and resistance to chemotherapy noticed in EGFR related epithelial tumors[16-19]. EGFR levels in normal cells usually ranges between 40000 and 100000 receptors per cell. Enhanced EGFR expression are a notable characteristic of many epithelial carcinomas like glioblastoma, Non-small cell lung cancer, breast, colorectal, bladder, prostate and ovarian carcinomas[11,16-19].
EGFR IN ORAL PHYSIOLOGY
To understand EGFR related pathogenesis a proper understanding of its significance in physiology needed. EGFR plays important roles in the development and maintenance of various oral structures, tooth development, eruption and morphogenesis.
Hernández et al in 1992 elicited the localization of epidermal growth factor and its receptor during tooth formation in rat embryos during embryonic days (E-16 to E-21) immunohistochemically. Another study by Heikinheimo et al on role of EGFR in tooth development and few neoplastic odontogenic neoplasms concluded that that regulation of EGFR expression is developmentally determined in human odontogenesis. Furthermore, the odontogenic epithelium is the main target tissue for EGF, TGF-β and TGF-α and they may also be involved in odontogenic tumorigenesis. Several authors like Wise et al, Shroff et al and Cdhill et al have proven that tooth follicle with the presence of EGFR and their ligands is essential for tooth eruption. EGFR and its ligands also mediates tooth morphogenesis as claimed by Hu et al.
On assessment of EGFR expression by Thesleff et al it was seen that they intensely bind to the epithelial cell rests of Malassez concluding that they are responsive to the actions of EGF. Her study speculated that these epithelial rests may be activated whenever there is local rise of EGF ligand in that tissue milieu. Another immunohistochemical analysis was performed in normal and pathological human gingival epithelia by Nordlund et al which showed that basal layers of gingival proliferating cells in inflamed adult periodontitis cases, as well as the epithelial cell rests of Malassez bound to the antibody intensely signifying that EGF moderates epithelial growth and differentiation in periodontal tissues.
Also in recent research by O Häärä et al it was evident that EGFR plays a role in formation of salivary gland by supporting the growth and development of the epithelium and survival of the mesenchyme.
EGFR IN ORAL PATHOLOGY
Various studies have analyzed EGFR expression in diverse oral lesions like squamous cell carcinomas[18,29-32], potentially malignant lesions[32-34], lichen planus[35,36] salivary gland tumors[37-39] and odontogenic cysts and tumours[40-44].
EGFR in head and neck squamous cell carcinoma
Head and neck squamous cell carcinoma (HNSCC) is increasing at an alarming rate with about 600000 patients being newly diagnosed annually. It was noted that most cases showing remission and metastasis are associated with poorer prognosis and a multitude of research is now being concentrated on understanding this disease and its relationship with EGFR pathways[18,19]. Heightened EGFR expression is observed in about 80%-90% HNSCC and often correlates with poorer prognosis, higher recurrence rate, advanced tumor stage and increased possibility of metastasis[13,18,19].
The HER 3 receptor was identified as most prognostic value in assessing tongue squamous cell carcinoma. EGFR has been a recent target of anticancer therapies due to its critical roles in cellular homeostasis. EGFR mutations are found in four exons of the EGFR gene, exons 18 to 21. Exon 19 deletions and exon 21 mutations account for most of these mutations. On genetic analysis it is seen that the EGFR mutation of deletion in exon 19 was implicated with squamous cell carcinoma development in few of the cases.
EGFR in potentially malignant lesions
EGFR over expression is an initial event in the squamous cell carcinoma of the head and neck carcinogenesis. On investigation done by Rautava et al in dysplastic, developing and malignant oral epithelium it was seen that all the four family of EGFR receptors was seen in developing oral epithelium and to a lesser extent in mature oral epithelium. An increase in EGFR immuno-reactivity was seen in 61% and 54% of dysplasias and OSCC respectively. Its increased presence is also noted in “apparently normal” mucosa from cancer patients, when compared to healthy controls (field cancerization) and this over expression is observed to steadily increase analogous to observed histological abnormalities, from dysplasia to carcinoma in situ. In normal mucosa EGFR positivity was seen only in the basal layers, whereas in leukoplakia the spinous and basal layers showed positivity and squamous cell carcinomas showed intense and increased positivity. Another similarly designed study in dysplasias and SCC showed nearly all cells of the dysplastic epithelium showing positivity and in oral squamous cell carcinomas, the positivity in the tumor cells correlated inversely with cellular differentiation. In other potentially malignant lesions like OSMF, it was found that there was a definite increase in EGFR expression along the differentiated layers of the oral epithelium. In certain lesions like lichen planus, increased EGFR expression in the epithelial cells as well as the infiltrating lymphocytes are hypothesized to play a significant role in disease development[35,36].
EGFR expression in salivary gland lesions
EGFR expression has also been analyzed in various salivary gland lesions[37-39]. In a studydone by Yamada et al 1989 the immunohistochemical localization of EGFR was classified into two types, one the cell membrane-positive type found in epithelial tumor cells, and the other is the cytoplasm positivity seen in normal ductal cells and luminal tumor cells of pleomorphic adenomas and mucoepidermoid carcinomas. In a recent study done on pleomorphic adenomas (PA), mucoepidermoid carcinoma (MC) and adenoid cystic carcinoma (ACC), it was found that all of them expressed EGFR family receptors. ErbB-2 was seen to be commonly expressed and both membrane and cytoplasmic staining is noted. Enhanced scores of ErbB-2 membrane were more common in MEC as compared to ACC and PA suggestive of their role in pathogenesis of salivary gland neoplasms. Another study done in carcinoma ex Pleomorphic adenoma (CXPA), showed intense EGFR expression in the outer borders of CXPA, indicating that this receptor may be related to cell detachment and invasive potential of CXPA.
EGFR expression in odontogenic lesions
Numerous investigations have been done in odontogenic epithelium and related lesions in reference to EGFR expression[40-44]. Based on the various studies conducted in odontogenic cysts and tumors and it has been suggested that EGFR is related to the proliferative mechanisms in these lesions. Shrestha was one of the first to study the expression of EGFR in odontogenic lesions and he found increased expression of EGFR in these odontogenic cysts and tumors but no positivity in ameloblastomas. Based on these findings the author then concluded that the proliferative pathways in ameloblastomas were diverse. However, most of the studies done later in ameloblastoma showed diverse results with most ameloblastomas giving EGFR positive immunoexpression[41,43]. EGFR expression was studied in the physiological odontogenic epithelium represented by the pericoronal follicle by da Silva Baumgart et al and he hypothesized that understanding the staining patterns of EGFR in the follicles could provide vital clues to the origin of various odontogenic cysts and tumors. Other studies by Vered et al and de Vicente et al also give diverse findings.
METHODS OF EVALUATION OF EGFR
EGFR quantification can be done at the DNA, RNA or protein level. EGFR mutations are known to occur in various carcinomas and they are studied by analyzing the chromosomes and DNA.EGFR amplification which is noted in various lesions can be studied by gene amplifications assay which analyze at the DNA, RNA and the protein levels in tissue[47,48]. mRNA based methods of detection are prone to problems with RNA degradation and contamination.
EGFR protein levels quantified by western blot analysis and enzyme immunoassay, measure total receptor protein and provide no data on their location in the cell. Immunohistochemistry is commonly used to evaluate EGFR protein levels and is arguably the most convenient method for analyzing clinical samples and give an idea about the cellular localization. However, the main disadvantage of immunohistochemistry is its lack of sensitivity and specificity in comparison to other methods. Further there is still no consensus of standard scoring criteria for the quantifying EGFR positivity in tissue specimens. Downstream markers and their analysis may also provide EGFR related information. The EGFR molecule has various downstream pathways of action and these molecules are of significance in studying specific lesions. Some of the most common downstream markers of significance are EGFR, p-EGFR, p-Akt, p-Erk, p-STAT3[50,51].
EGFR AND ITS CLINICAL IMPLICATIONS
The identification of chemo-therapeutic agents in the treatment of specific malignancies like leukemias and lymphomas have simplified and inspired new treatment perspectives of neoplasms. Since the advent and success of these treatment strategies, researchers all over the world are trying to open more avenues in the treatment of other malignancies. Ever since the discovery of EGF in 1960 and the isolation of EGFR by Cohen et al in 1980 numerous studies are done to elucidate its role in cancer pathogenesis.Based on the work of many pioneers on EGFR agents John Mendelsohn conducted research focusing on EGFR and proposed EGFR as an anticancer target, especially in various carcinomas[17,53]. Control of EGFR signaling is likely to open new avenues of treatment in three main areas that include cell yield, organ restoration and management of cancer.
EGFR is the receptor most often found up regulated and its gene mutations are evident in a wide variety of human tumors like head and neck cancers, renal carcinomas, breast carcinomas, gliomas, colon cancers, non-small-cell lung carcinomas and pancreatic carcinomas[7,13,18,19,30,45,54,55]. Herbst et al in 2002 stated that EGFR is one of the most important receptors critical for cell proliferation, differentiation and survival and related its dysregulation to be of significance in suppressing apoptosis, mediating neoplastic angiogenesis, increasing metastatic ability and resisting chemo and radiotherapy. Several ongoing clinical trials on humans are presently testing anti-EGFR antibodies with many of them showing promising results for the future. The rationale behind EGFR therapies is that they compete with endogenous growth factors like EGF and transforming growth factor-alpha, for binding sites. Once bound EGFR blocks crucial downstream pathways thereby interfering with the growth of neoplasms expressing EGFR.
The rationale of using anti-EGFR agents in head and neck cancers is that EGFR is expressed in more than 90% of head and neck carcinomas and studies have shown that EGFR over expression is associated with decreased survival[1,18,29-32,49]. Also it is noted that increased EGFR expression occurs initially in carcinogenesis and is present even in premalignant oral lesions[32-34].Finally studies have also shown that inhibition of EGFR-TK pathway slows the growth of xenograft tumour models of head and neck. EGFR based chemotherapy can involve various methods. This can be achieved by using directly acting anti-EGFR agents, by using tyrosine kinase inhibitors (TKIs) or agents that inhibit the downstream molecules in the EGFR pathway. Amongst these, EGFR antibody Cetuximab and TKIs like Erlotinib and Gefitinib are being trialled in HNSCC. Understanding the molecular pathogenesis of the neoplasm will help in choosing the ideal therapeutic agent. For example EGFRvIII is caused by frame deletion mutations and is seen in 42% of HNSCC leading to growth of the tumor and provides resistance to antibody based treatment interventions.
In such situations, patients with EGFRvIII HNSCCs would possibly benefit better from tyrosine kinase inhibitors rather than EGFR antibody based treatment strategies[56,57].
Another important treatment possibility of the EGFR neoplasms is that anti-EGFR agents increase the radiosensitivity of several neoplasms. In a recent randomised phase III clinical trial attempted by Bonner et al it was seen that simultaneous radiotherapy and chemotherapy with Cetuximab in head and neck cancer patients showed improved local tumour containment compared to radiotherapy alone. The cause for increased radiation effects when combined with EGFR therapy are still obscure. Numerous other studies studying the efficacy of anti- EGFR agents are in the phase three trial[1,7,54,55,58]. Antisense oligonucleotides, ligand conjugates and immunoconjugates of EGFR are also used to inhibit EGFR activity. Other EGFR inhibitors like cetuximab-C225 are being extensively studied in head and neck carcinomas and are in the third phase of trial. However till date no drastic changes in treatment modalities have been experienced. Moreover, there are a lot of side effects associated with the use of EGFR which has rendered it use, unacceptable.
Vered in his article mentions that adverse effects of anti-EGFR agents like C225 and ZD-1839 is usually observed in less than 15% of patients, and these effects may not occur with ameloblastoma, as these side effects could be avoided by intralesional administration of the anti-EGFR agents. Recently, a fully human anti-EGFR monoclonal antibody, vectibix-EGF was developed as a possible treatment for surgically compromised cases of ameloblastoma. However, clinical trials are yet to take place.
The EGF receptor is an important molecule in maintaining various pathways and homeostasis within an organism. It plays varied roles and its dysregulation is identified to be a key factor in various oral pathologies, especially HNSCC and ameloblastomas. Identifying ideal therapeutic target will enable the transition of treating these lesions using a non surgical modality thereby significantly reducing the mortality and morbidity of the patient. The receptor mediates it action through various pathways and the proper understanding of these will enable us to develop ideal treatment strategies to combat the various lesions. Several studies are now targeting these pathways, however, till now significant success has not been achieved in clinical trials using anti-EGFR agents in HNSCC. Several reasons suggested for this insensitivity are the multifactorial aetiology of head and neck carcinomas and lack of proper understanding of the various molecular pathways. More research needs to be focussed on the understanding of this molecule in future in order to bring the treatment of several debilitating neoplasms from the bench to the bedside.
1 Bianco R, Gelardi T, Damiano V, Ciardiello F, Tortora G. Rational bases for the development of EGFR inhibitors for cancer treatment. Int J Biochem Cell Biol 2007; 39: 1416-1431 [PMID: 17596994]
2 Wells A. EGF receptor. Int J Biochem Cell Biol 1999; 31: 637-643 [PMID: 10404636]
3 EGFR epidermal growth factor receptor [Homo sapiens] Gene ID: 1956 [Updated on 2012 May 11]. Available from: URL: http: //www.ncbi.nlm.nih.gov/gene/1956
7 Yarden Y. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer 2001; 37 Suppl 4: S3-S8 [PMID: 11597398]
8 Henson ES, Gibson SB. Surviving cell death through epidermal growth factor (EGF) signal transduction pathways: implications for cancer therapy. Cell Signal 2006; 18: 2089-2097 [PMID: 16815674]
9 Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 2002; 285: 1-24 [PMID: 12039028]
10 Ladanyi M, Pao W. Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond. Mod Pathol 2008; 21 Suppl 2: S16-S22 [PMID: 18437168]
11 Damjanov I, Mildner B, Knowles BB. Immunohistochemical localization of the epidermal growth factor receptor in normal human tissues. Lab Invest 1986; 55: 588-592 [PMID: 3534450]
12 Yi T, Lee HL, Cha JH, Ko SI, Kim HJ, Shin HI, Woo KM, Ryoo HM, Kim GS, Baek JH. Epidermal growth factor receptor regulates osteoclast differentiation and survival through cross-talking with RANK signaling. J Cell Physiol 2008; 217: 409-422 [PMID: 18543257]
13 Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer 2001; 37 Suppl 4: S9-15 [PMID: 11597399]
14 Gibson EM, Henson ES, Haney N, Villanueva J, Gibson SB. Epidermal growth factor protects epithelial-derived cells from tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by inhibiting cytochrome c release. Cancer Res 2002; 62: 488-496 [PMID: 11809700]
15 Weihua Z, Tsan R, Huang WC, Wu Q, Chiu CH, Fidler IJ, Hung MC. Survival of cancer cells is maintained by EGFR independent of its kinase activity. Cancer Cell 2008; 13: 385-393 [PMID: 18455122 DOI: 10.1016/j.ccr.2008.03.015]
16 Ciardiello F, Tortora G. Epidermal growth factor receptor (EGFR) as a target in cancer therapy: understanding the role of receptor expression and other molecular determinants that could influence the response to anti-EGFR drugs. Eur J Cancer 2003; 39: 1348-1354 [PMID: 12826036]
17 Mendelsohn J, Baselga J. Epidermal growth factor receptor targeting in cancer. Semin Oncol 2006; 33: 369-385 [PMID: 16890793]
18 Ford AC, Grandis JR. Targeting epidermal growth factor receptor in head and neck cancer. Head Neck 2003; 25: 67-73 [PMID: 12478546]
19 Scaltriti M, Baselga J. The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res 2006; 12: 5268-5272 [PMID: 17000658]
20 Hernández LC, Cobo J, del Valle ME, Vijande M, Vega JA. Immunohistochemical localization of epidermal growth factor and its receptor during odontogenesis in the rat. Eur J Orthod 1992; 14: 333-338 [PMID: 1397071]
21 Heikinheimo K, Voutilainen R, Happonen RP, Miettinen PJ. EGF receptor and its ligands, EGF and TGF-alpha, in developing and neoplastic human odontogenic tissues. Int J Dev Biol 1993; 37: 387-396 [PMID: 8292533]
22 Wise GE, Lin F, Fan W. Localization of epidermal growth factor and its receptor in mandibular molars of the rat prior to and during prefunctional tooth eruption. Dev Dyn 1992; 195: 121-126 [PMID: 1297454]
23 Shroff B, Kashner JE, Keyser JD, Hebert C, Norris K. Epidermal growth factor and epidermal growth factor-receptor expression in the mouse dental follicle during tooth eruption. Arch Oral Biol 1996; 41: 613-617 [PMID: 8937653]
24 Cahill DR, Marks SC. Tooth eruption: evidence for the central role of the dental follicle. J Oral Pathol 1980; 9: 189-200 [PMID: 6777476]
25 Hu CC, Sakakura Y, Sasano Y, Shum L, Bringas P, Werb Z, Slavkin HC. Endogenous epidermal growth factor regulates the timing and pattern of embryonic mouse molar tooth morphogenesis. Int J Dev Biol 1992; 36: 505-516 [PMID: 1295561]
26 Thesleff I. Epithelial cell rests of Malassez bind epidermal growth factor intensely. J Periodontal Res 1987; 22: 419-421 [PMID: 2961874]
27 Nordlund L, Hormia M, Saxén L, Thesleff I. Immunohistochemical localization of epidermal growth factor receptors in human gingival epithelia. J Periodontal Res 1991; 26: 333-338 [PMID: 1831500]
28 Häärä O, Koivisto T, Miettinen PJ. EGF-receptor regulates salivary gland branching morphogenesis by supporting proliferation and maturation of epithelial cells and survival of mesenchymal cells. Differentiation 2009; 77: 298-306 [PMID: 19272528 DOI: 10.1016/j.diff.2008.10.006]
29 O-charoenrat P, Rhys-Evans PH, Modjtahedi H, Eccles SA. The role of c-erbB receptors and ligands in head and neck squamous cell carcinoma. Oral Oncol 2002; 38: 627-640 [PMID: 12167415]
30 Zimmermann M, Zouhair A, Azria D, Ozsahin M. The epidermal growth factor receptor (EGFR) in head and neck cancer: its role and treatment implications. Radiat Oncol 2006; 1: 11 [PMID: 16722544]
31 Del Sordo R, Angiero F, Bellezza G, Cavaliere A, Mameli MG, Stefani M, Dessy E, Sidoni A. HER family receptors expression in squamous cell carcinoma of the tongue: study of the possible prognostic and biological significance. J Oral Pathol Med 2010; 39: 79-86 [PMID: 19691460 DOI: 10.1111/j.1600-0714.2009.00815.x]
32 Bagan JV, Mata-Roig M, Cortio-Gimeno J, Murillo-Cortes J, Hens-Aumente E, Poveda-Roda R, Bagan L. Epidermal growth factor receptor copy number in potentially malignant oral disorders and oral squamous cell carcinoma: a short communication and preliminary study. J Oral Pathol Med 2012; 41: 662-666 [PMID: 22417006 DOI: 10.1111/j.1600-0714.2012.01137.x]
33 Srinivasan M, Jewell SD. Quantitative estimation of PCNA, c-myc, EGFR and TGF-alpha in oral submucous fibrosis--an immunohistochemical study. Oral Oncol 2001; 37: 461-467 [PMID: 11377235]
34 Rautava J, Jee KJ, Miettinen PJ, Nagy B, Myllykangas S, Odell EW, Soukka T, Morgan PR, Heikinheimo K. ERBB receptors in developing, dysplastic and malignant oral epithelia. Oral Oncol 2008; 44: 227-235 [PMID: 17604679]
35 Ebrahimi M, Boldrup L, Wahlin YB, Coates PJ, Nylander K. Decreased expression of the p63 related proteins beta-catenin, E-cadherin and EGFR in oral lichen planus. Oral Oncol 2008; 44: 634-638 [PMID: 17936670]
36 Kumagai K, Horikawa T, Gotoh A, Yamane S, Yamada H, Kobayashi H, Hamada Y, Suzuki S, Suzuki R. Up-regulation of EGF receptor and its ligands, AREG, EREG, and HB-EGF in oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 110: 748-754 [PMID: 20952227 DOI: 10.1016/j.tripleo.2010.06.022]
37 Yamada K, Iwai K, Okada Y, Mori M. Immunohistochemical expression of epidermal growth factor receptor in salivary gland tumours. Virchows Arch A Pathol Anat Histopathol 1989; 415: 523-531 [PMID: 2508310]
38 Ito FA, Ito K, Coletta RD, Graner E, de Almeida OP, Lopes MA. Salivary gland tumors: immunohistochemical study of EGF, EGFR, ErbB-2, FAS and Ki-67. Anal Quant Cytol Histol 2009; 31: 280-287 [PMID: 20701095]
39 Furuse C, Miguita L, Rosa AC, Soares AB, Martinez EF, Altemani A, de Araújo VC. Study of growth factors and receptors in carcinoma ex pleomorphic adenoma. J Oral Pathol Med 2010; 39: 540-547 [PMID: 20149060 DOI: 10.1111/j.1600-0714.2009.00858.x]
40 Shrestha P, Yamada K, Higashiyama H, Takagi H, Mori M. Epidermal growth factor receptor in odontogenic cysts and tumors. J Oral Pathol Med 1992; 21: 314-317 [PMID: 1522533]
41 de Oliveira MG, Lauxen Ida S, Chaves AC, Rados PV, Sant’Ana Filho M. Odontogenic epithelium: immunolabeling of Ki-67, EGFR and survivin in pericoronal follicles, dentigerous cysts and keratocystic odontogenic tumors. Head Neck Pathol 2011; 5: 1-7 [PMID: 21053110 DOI: 10.1007/s12105-010-0216-0]
42 da Silva Baumgart C, da Silva Lauxen I, Filho MS, de Quadros OF. Epidermal growth factor receptor distribution in pericoronal follicles: relationship with the origin of odontogenic cysts and tumors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007; 103: 240-245 [PMID: 17234542]
43 Vered M, Shohat I, Buchner A. Epidermal growth factor receptor expression in ameloblastoma. Oral Oncol 2003; 39: 138-143 [PMID: 12509966]
44 de Vicente JC, Torre-Iturraspe A, Gutiérrez AM, Lequerica-Fernández P. Immunohistochemical comparative study of the odontogenic keratocysts and other odontogenic lesions. Med Oral Patol Oral Cir Bucal 2010; 15: e709-e715 [PMID: 20383104]
45 Eberhard DA, Giaccone G, Johnson BE. Biomarkers of response to epidermal growth factor receptor inhibitors in Non-Small-Cell Lung Cancer Working Group: standardization for use in the clinical trial setting. J Clin Oncol 2008; 26: 983-994 [PMID: 18281673]
46 Gombos Z, Danihel L, Puttaswamy K, Brose M. A comparative study of EGFR mutation screening methods in non-small cell carcinoma of lung. Bratisl Lek Listy 2010; 111: 365-368 [PMID: 20806539]
47 Hirsch FR, Varella-Garcia M, McCoy J, West H, Xavier AC, Gumerlock P, Bunn PA, Franklin WA, Crowley J, Gandara DR. Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group Study. J Clin Oncol 2005; 23: 6838-6845 [PMID: 15998906]
48 Tsugu A, Kijima H, Yamazaki H, Ohnishi Y, Takamiya Y, Abe Y, Ueyama Y, Sato O, Tamaoki N, Nakamura M. Localization of aberrant messenger RNA of epidermal growth factor receptor (EGFR) in malignant glioma. Anticancer Res 1997; 17: 2225-2232 [PMID: 9216693]
49 Thariat J, Etienne-Grimaldi MC, Grall D, Bensadoun RJ, Cayre A, Penault-Llorca F, Veracini L, Francoual M, Formento JL, Dassonville O, De Raucourt D, Geoffrois L, Giraud P, Racadot S, Morinière S, Milano G, Van Obberghen-Schilling E. Epidermal growth factor receptor protein detection in head and neck cancer patients: a many-faceted picture. Clin Cancer Res 2012; 18: 1313-1322 [PMID: 22228639 DOI: 10.1158/1078-0432.CCR-11-2339]
50 Han SW, Hwang PG, Chung DH, Kim DW, Im SA, Kim YT, Kim TY, Heo DS, Bang YJ, Kim NK. Epidermal growth factor receptor (EGFR) downstream molecules as response predictive markers for gefitinib (Iressa, ZD1839) in chemotherapy-resistant non-small cell lung cancer. Int J Cancer 2005; 113: 109-115 [PMID: 15386420]
51 Gori S, Sidoni A, Colozza M, Ferri I, Mameli MG, Fenocchio D, Stocchi L, Foglietta J, Ludovini V, Minenza E, De Angelis V, Crinò L. EGFR, pMAPK, pAkt and PTEN status by immunohistochemistry: correlation with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab. Ann Oncol 2009; 20: 648-654 [PMID: 19188134 DOI: 10.1093/annonc/mdn681]
52 Cohen S, Carpenter G, King L. Epidermal growth factor-receptor-protein kinase interactions. Co-purification of receptor and epidermal growth factor-enhanced phosphorylation activity. J Biol Chem 1980; 255: 4834-4842 [PMID: 6246084]
54 Chintala L, Kurzrock R. Epidermal growth factor receptor mutation and diverse tumors: case report and concise literature review. Mol Oncol 2010; 4: 306-308 [PMID: 20346742 DOI: 10.1016/j.molonc.2010.03.002]
55 Herbst RS, Shin DM. Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy. Cancer 2002; 94: 1593-1611 [PMID: 11920518]
56 Howard JD, Lu B, Chung CH. Therapeutic targets in head and neck squamous cell carcinoma: identification, evaluation, and clinical translation. Oral Oncol 2012; 48: 10-17 [PMID: 22020057 DOI: 10.1016/j.oraloncology.2011.09.013]
57 Loeffler-Ragg J, Schwentner I, Sprinzl GM, Zwierzina H. EGFR inhibition as a therapy for head and neck squamous cell carcinoma. Expert Opin Investig Drugs 2008; 17: 1517-1531 [PMID: 18808311 DOI: 10.1517/135437184.108.40.2067]
58 Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010; 11: 21-28 [PMID: 19897418 DOI: 10.1016/S1470-2045(09)70311-0]
P- Reviewer: Dereci O S- Editor: Ji FF L- Editor: A E- Editor: Jiao XK