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• W2099109744 abstract "Biomarkers in MedicineVol. 4, No. 6 General content - EditorialFree AccessUsing biomarkers to detect oral cancer holds potential for saving lives when the cancer is most curableGe JinGe JinDepartment of Biological Sciences, Case Western Reserve University School of Dental Medicine, 10900 Euclid Avenue, Cleveland, OH 44106-4905, USA. Search for more papers by this authorEmail the corresponding author at ge.jin@case.eduPublished Online:6 Dec 2010https://doi.org/10.2217/bmm.10.105AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: biomarkercarcinoma in situdefensinsleukoplakiaoral cancerOral squamous cell carcinoma (OSCC) comprises approximately 3–5% of all malignancies in the USA, corresponding to 40,490 new cases and approximately 10,000 deaths each year [1–3]. Despite significant advances in therapeutics and early diagnosis, the expected 5-year relative survival rate of oral cancer has improved only marginally over the past decade [1–3]. Early diagnosis of oral cancer plays a key role in disease progression, treatment response, and ultimately, quality of life and patient survival. Therefore, biomarkers for risk prediction of oral cancer hold much promise in this respect. Various oral lesions, including leukoplakia, erythroplakia, lechen planus and submucous fibrosis, are considered potentially malignant oral disorders that may contain precancerous cells, which could malignantly transform [4]. Currently, these lesions are treated surgically, with or without cellular and tissue changes (dysplasia). However, it is unknown if surgery can really prevent transformation into OSCC. Although the term “potentially malignant disorders” was recommended by the WHO to describe precancerous lesions, the clinical and histological features alone cannot accurately predict whether these precancers of the oral mucosa remain stable, regress or progress to malignancy [5]. Furthermore, evaluation of an asymptomatic patient for early-stage cancer, based on its physical features alone, is frequently compromised because malignant and benign lesions may not be clinically distinguishable [6]. Consequently, approximately 60% of oral cancers are advanced by the time they are detected, and approximately 15% of patients have another cancer in a nearby area such as the larynx, esophagus or lungs [7,8]. Therefore, there is a need to identify and use molecular biomarkers to evaluate individuals with potentially malignant disorders who are at a high risk of developing OSCC and those with early-stage malignant lesions.A variety of genetic and molecular signatures of precancerous lesions and OSCC have been identified as tumor biomarkers. However, these biomarkers have, so far, not gained any use in routine diagnosis and risk assessment of oral cancer [5,9]. Malignant transformation or progression to OSCC requires multiple genetic alternations and involves a variety of stromal cells, such as macrophages, in the tumor microenvironment [10]. Therefore, identification of molecular markers that can predict disease progression and techniques that can readily use such biomarkers in routine practices will improve the management of these disorders.Potentially malignant disorders & oral cancerPotentially malignant disorders are currently referred to as all clinical entities that carry a risk of cancer with widespread anatomical distribution. In this regard, leukoplakia is a clinical presentation that is defined by the WHO as a “white patch or plaque that cannot be characterized clinically or pathologically as any other disease” and is, by far, the most common precancer, accounting for over 80% of potentially malignant oral disorders [4,11,12]. In addition, leukoplakia is also a relatively common oral lesion, ranging from 1 to 5% in the general population [12]. However, it does not have the highest malignant transformation risk among precancerous lesions. Oral erythroplakia, a relatively rare (reported incidence: 0.02–0.80%) red lesion of the oral cavity that cannot be removed, has a much higher malignant transformation risk than leukoplakia; up to 50% of these lesions are invasive OSCC and 40% are carcinoma in situ[12,13]. Risk assessment of precancerous lesions, such as leukoplakia, is currently performed based on the histological criteria of cellular proliferation, maturation of the epithelium and cellular atypia, and graded as mild, moderate and severe dysplasia. However, lack of objectivity of the established histological criteria and difficulties in predicting the outcome of individual cases calls for the identification and practical application of reliable biomarkers [5].Molecular biomarkers & histological assessmentAlternations in genes and pathways that regulate cellular signaling, cell cycle, differentiation, apoptosis, genomic stability, motility, angiogenesis and metastasis are significantly associated with development and progression of a potentially malignant disorder to OSCC [5,9]. Aberrant expression and function of molecules involved in these signaling networks have been considered as biomarkers for risk assessment of malignant transformation. These biomarkers, including oncogenes (EGF receptor [EGFR], EGF, RAS and MYC), tumor suppressor genes (p53, 21, 27 and 16) and proliferation markers (Ki67 and proliferating cell nuclear antigen), have been analyzed from fixed biopsies, on homogenized tissue samples and in body fluid, such as saliva. However, spatial and temporal presentation of these molecules in precancerous lesions and OSCC often matches up with histological assessment, which may limit their use as biomarkers in routine practice. For example, enhanced expression and activation of the EGFR family and its ligands, EGF and TGF-α, have been associated with precancerous leukoplakia [5,11]. EGFR is detected in proliferative cells of the basal layer in normal oral mucosa and leukoplakia with mild, moderate and severe dysplastic lesions [5,11,13]. Interestingly, the pattern of EGFR expression in dysplastic leukoplakia coincides with the histological assessment of dysplasia in these lesions.Dysfunction of the p53 pathway, frequently through mutations and loss of heterozygosity, has been associated with early head and neck carcinogenesis, and can be detected in precancerous lesions [5]. Mutant p53 proteins have a prolonged half-life. Therefore, they are readily detected in biopsies using immunohistochemistry [5]. Similar to the pattern of EGFR expression in dysplasia, the expression of p53 protein can be identified in dysplastic lesions with features that recapitulate histological evaluation [5,14,15]. Therefore, these biomarkers may serve as adjuncts to histological assessment of malignant transformation. However, their application in routine practice are limited and not defined.Human β-defensins as biomarkers for OSCCRecent progress in molecular oncology and cancer biology has demonstrated that accumulation of genetic alterations drives the progression of dysplastic/neoplastic lesions to highly malignant derivatives, a process not only involving tumor cells, but also many other nonmalignant cell types, including innate and adaptive immune cells, fibroblasts, epithelial cells and endothelial cells, in the tumor microenvironment [16,17]. Tumor cell-derived molecules, such as chemokines and proangiogenic factors, play a critical role in initiation, maintenance and expansion of the protumor environment. Therefore, these molecules may have the potential to serve as biomarkers for routine application.Kawsar et al. have demonstrated that human β-defensins (hBDs) are spatiotemporally expressed in normal, dysplasia, carcinoma in situ and OSCC biopsies [18]. hBDs are small secreted peptides, originally identified from the plasma of patients with renal disease and from psoriatic skin lesions as antimicrobial molecules of innate immunity [19–21]. Oral epithelia express hBD-1, -2 and -3. hBD-1 appears to be constitutively expressed in oral epithelial cells [22]. In oral epithelial and gastric cells, hBD-2 induction has been demonstrated to require activation of NF-κB transcription factor [23,24], while hBD-3 expression is induced by EGF via MEK1/2, protein kinase C, PI3K and p38 MAPK signaling cascades in oral epithelial cells [18]. In normal oral epithelia, co-expression of hBD-1 and -2 is primarily associated with differentiated epithelial cells in the superficial layers, whereas hBD-3 is predominantly produced by proliferative cells in the basal layer [18,25]. In moderate dysplasia, tissue distribution of hBD-2 and -3 is correlated with dysplastic cells in the lesion [18]. However, in carcinoma in situ biopsies, the entire lesion site expresses hBD-3, with little to no expression of hBD-1 and -2 [10,18]. Overexpression of hBD-3 in oral cancer has also been confirmed by a clinical study [26]. Furthermore, hBD-3 promotes macrophage infiltration and tumorigenicity in nude mice, recruits monocytes via the chemokine receptor CCR2 and stimulates the expression of tumor-promoting cytokines in macrophages [10,18]. These results suggest that the overexpression of hBD-3 and loss of hBD-2 in neoplastic cells of oral carcinoma in situ may serve as a signature of oncogene activation, leading to cellular transformation and precancerous lesions. In addition, hBD-3 is a secreted peptide and, once produced by precancerous lesions, it may enter the circulation and be readily detected in blood, saliva and other body fluids. Therefore, a noninvasive, moderate-cost screening protocol can be developed for risk assessment of malignant transformation.Oral squamous cell carcinoma is initiated from stem cells of the basal layer of the epithelium that have acquired genetic alterations, such as activating mutations or amplification of oncogenes, as well as inactivation of tumor suppressor genes [27–29]. Although aberrant expression of these genes are etiologically relevant to oral carcinogenesis, dysfunctional regulation of many other molecules, which are either modulated by or interact with those genes, play crucial roles in promoting malignant transformation and cancer progression. Therefore, identification of biomarkers that are involved in different aspects of oral carcinogenesis will significantly increase sensitivity, predictability and reproducibility in risk assessment of malignant transformation.Recent progress in high-throughput techniques, including the profiling of gene expression (microarray), detection of single-nucleotide changes of preselected genes, miRNA analysis and salivary proteomics, will greatly promote identification and development of novel biomarkers that distinguish normal oral epithelia from potentially malignant lesions and early-stage oral cancer. Further validation of these biomarkers and application in combination with routine histological studies will lead to improved diagnostic approaches and therapeutic strategies when the cancer is most curable.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Bibliography1 Jemal A, Siegel R, Ward E et al.: Cancer statistics, 2006. CA Cancer J. 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Science278,1812–1815 (1997).CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByRoles of Antimicrobial Peptides in Gynecological Cancers3 September 2022 | International Journal of Molecular Sciences, Vol. 23, No. 17Do Stemness Markers in Oral Erythroplakia Have a Role in Malignant Transformation: A Comprehensive Review24 November 2021 | World Journal of Dentistry, Vol. 12, No. 6Nonsurgical treatment of oral cavity leukoplakiaMatrix Science Medica, Vol. 4, No. 4Salivary L-fucose as a biomarker for oral potentially malignant disorders and oral cancerJournal of Cancer Research and Therapeutics, Vol. 16, No. 3Human antimicrobial peptides and cancerSeminars in Cell & Developmental Biology, Vol. 88Prognostic role of epidermal growth factor receptor in head and neck cancer: A meta-analysis13 September 2013 | Journal of Surgical Oncology, Vol. 108, No. 6Personalized oral health careThe Journal of the American Dental Association, Vol. 143, No. 2 Vol. 4, No. 6 Follow us on social media for the latest updates Metrics History Published online 6 December 2010 Published in print December 2010 Information© Future Medicine LtdKeywordsbiomarkercarcinoma in situ defensinsleukoplakiaoral cancerFinancial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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