Despite commendable progress in the prevention, detection, and treatment of a wide variety of solid tumor types, oral squamous cell carcinoma (OSCC) remains a significant health burden across the globe. OSCC carcinogenesis involves accumulation of genetic alterations that coincide with the multistep malignant transformation of normal oral epithelium. OSCC is often first diagnosed at late stages of the disease (advanced regional disease and/or metastasis). Delayed diagnosis precludes successful treatment and favorable outcomes. In clinical practice, opportunities exist to identify patients with oral potentially malignant disorders (OPMDs), which precede the development of cancer. This review addresses the current status of laboratory and clinical research on OPMDs, with emphasis on leukoplakia and erythroplakia. OSF is also presented, though there is a paucity of published studies on this disorder. We focus on findings that could translate into earlier diagnosis and more efficacious treatment of those lesions with significant malignant potential. We explore how markers of OPMD malignant transformation might be implemented into current diagnostic practice to help clinicians objectively stratify patients into treatment/follow-up groups according to relative risk. We provide an overview of recently concluded and ongoing OPMD chemoprevention trials. We describe laboratory OPMD models that can be used to not only to reveal the genetic and molecular intricacies of oral cancer but also to develop novel screening methods and therapeutic approaches. Finally, we call for targeted screening programs of at-risk populations in order to facilitate diagnosis and treatment of OPMD and early OSCC.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.28754

Potentially malignant disorders of the oral cavity: current practice and future directions in the clinic and laboratory.

Betel nut (BN), betel quid (BQ) and products derived from them are widely used as a socially endorsed masticatory product The addictive nature of BN/BQ has resulted in its widespread usage making it the fourth most abused substance by humans Progressively, several additives, including chewing tobacco, got added to simple BN preparations This addictive practice has been shown to have strong etiological correlation with human susceptibility to cancer, particularly oral and oropharyngeal cancers

The PUBMED database was searched to retrieve all relevant published studies in English on BN and BQ, and its association with oral and oropharyngeal cancers Only complete studies directly dealing with BN/BQ induced carcinogenesis using statistically valid and acceptable sample size were analyzed Additional relevant information available from other sources was also considered

This systematic review attempts to put in perspective the consequences of this widespread habit of BN/BQ mastication, practiced by approximately 10% of the world population, on oral cancer with a clinical perspective BN/BQ mastication seems to be significantly associated with susceptibility to oral and oropharyngeal cancers Addition of tobacco to BN has been found to only marginally increase the cancer risk Despite the widespread usage of BN/BQ and its strong association with human susceptibility to cancer, no serious strategy seems to exist to control this habit The review, therefore, also looks at various preventive efforts being made by governments and highlights the multifaceted intervention strategies required to mitigate and/or control the habit of BN/BQ mastication

/pdf/association-of-betel-nut-with-carcinogenesis-revisit-with-a-847zwe5768.pdf

Association of betel nut with carcinogenesis: revisit with a clinical perspective.

Oral submucous fibrosis (OSF) is a chronic inflammatory disease characterized by the accumulation of excess collagen, and areca nut chewing has been proposed as an important etiological factor for disease manifestation. Activation of transforming growth factor-β signaling has been postulated as the main causative event for increased collagen production in OSF. Oral epithelium plays important roles in OSF, and arecoline has been shown to induce TGF-β in epithelial cells. In an attempt to understand the role of areca nut constituents in the manifestation of OSF, we studied the global gene expression profile in epithelial cells (HaCaT) following treatment with areca nut water extract or TGF-β. Interestingly, 64% of the differentially regulated genes by areca nut water extract matches with the TGF-β induced gene expression profile. Out of these, expression of 57% of genes was compromised in the presence of ALK5 (TβRI) inhibitor and 7% were independently induced by areca nut, highlighting the importance of TGF-β in areca nut actions. Areca nut water extract treatment induced p-SMAD2 and TGF-β downstream targets in HaCaT cells but not in human gingival fibroblast cells (hGF), suggesting epithelial cells could be the source of TGF-β in promoting OSF. Water extract of areca nut consists of polyphenols and alkaloids. Both polyphenol and alkaloid fractions of areca nut were able to induce TGF-β signaling and its downstream targets. Also, SMAD-2 was phosphorylated following treatment of HaCaT cells by Catechin, Tannin and alkaloids namely Arecoline, Arecaidine and Guvacine. Moreover, both polyphenols and alkaloids induced TGF-β2 and THBS1 (activator of latent TGF-β) in HaCaT cells suggesting areca nut mediated activation of p-SMAD2 involves up-regulation and activation of TGF-β. These data suggest a major causative role for TGF-β that is induced by areca nut in OSF progression.

/pdf/activation-of-tgf-b-pathway-by-areca-nut-constituents-a-5e28ob1t66.pdf

Activation of TGF-β Pathway by Areca Nut Constituents: A Possible Cause of Oral Submucous Fibrosis

Oral submucous fibrosis (OSF) is a chronic, insidious disease characterized by progressive submucosal fibrosis of the oral cavity and the oropharynx. People affected by this disease mostly live in south Asia, but migrants from these countries to the United States and Europe may present with OSF. We provide a historical background of the disease, and the objective of this review is to update the current knowledge on the etiology and etiopathogenesis of OSF.

/pdf/oral-submucous-fibrosis-a-historical-perspective-and-a-42y4tmehpa.pdf

Oral submucous fibrosis: a historical perspective and a review on etiology and pathogenesis

To understand the molecular pathogenesis of oral submucous fibrosis (OSF), which is a chronic inflammatory disease, gene expression profiling was performed in 10 OSF tissues against 8 pooled normal tissues using oligonucleotide arrays. Microarray results revealed differential expression of 5,288 genes (P ≤ 0.05 and fold change ≥ 1.5). Among these, 2,884 are upregulated and 2,404 are downregulated. Validation employing quantitative real-time PCR and immunohistochemistry confirmed upregulation of transforming growth factor-β1 (TGF-β1), TGFBIp, THBS1, SPP1, and TIG1 and downregulation of bone morphogenic protein 7 (BMP7) in OSF tissues. Furthermore, activation of TGF-β pathway was evident in OSF as demonstrated by pSMAD2 strong immunoreactivity. Treatment of keratinocytes and oral fibroblasts by TGF-β confirmed the regulation of few genes identified in microarray including upregulation of connective tissue growth factor, TGM2, THBS1, and downregulation of BMP7, which is a known negative modulator of fibrosis. Taken together, these data suggest activation of TGF-β signaling and suppression of BMP7 expression in the manifestation of OSF.

Role of TGF-β and BMP7 in the pathogenesis of oral submucous fibrosis.

Background: Epidemiological data have shown an association of areca nut chewing with oral submucous fibrosis (OSF) Experimental evidence to confirm this has been limited Fibrosis-promoting activity of areca nut was tested in an animal model



Method:  Buccal mucosa of a group of 20 female BALB/c strain mice, 10–12 weeks of age, was treated twice daily 6 days per week with topical application of aqueous areca nut extracts for 300–600 days A control group (n = 20) was treated with 50 mM NaCl The influence of areca nut on the oral epithelium and connective tissue was recorded semiquantitatively by light microscopy



Results:  The areca nut-treated oral epithelium showed progressive changes in epithelial thickness leading to atrophy, increased cellularity of fibroblasts, fibrosis of connective tissue, focal infiltration of inflammatory cells and muscle atrophy On killing after 600 days of treatment, the scores on cellularity, inflammation and muscle atrophy were significantly different to the control group (P = 003)



Conclusion:  The study provides further evidence that areca nut contributes to the development of OSF in treated animals The model has the potential to test synergism of areca nut with other carcinogens and any therapeutic interventions

P. Amaratunga

Papers

Development of an in vivo mouse model to study oral submucous fibrosis.