Carcinogenesis of the Oral Cavity: Environmental Causes and Potential Prevention by Black Raspberry

Abstract

Worldwide, cancers of the oral cavity and pharynx comprise the sixth most common malignancies. Histologically, more than 90% of oral cancers are squamous cell carcinoma (SCC). Epidemiologic data strongly support the role of exogenous factors such as tobacco, alcohol, and human papilloma virus infection as major causative agents. Avoidance of risk factors has only been partially successful, and survival rates have not improved despite advances in therapeutic approaches. Therefore, new or improved approaches to prevention and/or early detection are critical. Better understanding of the mechanisms of oral carcinogenesis can assist in the development of novel biomarkers for early detection and strategies for disease prevention. Toward this goal, several animal models for carcinogenesis in the oral cavity have been developed. Among these are xenograft, and transgenic animal models, and others employing the synthetic carcinogens such as 7,12-dimethylbenz[a]anthracene in hamster cheek pouch and 4-nitroquinoline-N-oxide in rats and mice. Additional animal models employing environmental carcinogens such as benzo[a]pyrene and N'-nitrosonornicotine have been reported. Each model has certain advantages and disadvantages. Models that (1) utilize environmental carcinogens, (2) reflect tumor heterogeneity, and (3) accurately represent the cellular and molecular changes involved in the initiation and progression of oral cancer in humans could provide a realistic platform. To achieve this goal, we introduced a novel nonsurgical mouse model to study oral carcinogenesis induced by dibenzo[a,l]pyrene (DB[a,l]P), an environmental pollutant and tobacco smoke constituent, and its diol epoxide metabolite (±)-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene [(±)-anti-DB[a,l]PDE]. On the basis of a detailed comparison of oral cancer induced by DB[a,l]P with that induced by the other above-mentioned oral carcinogens with respect to dose, duration, species and strain, cellular and molecular targets, and relative carcinogenic potency, our animal model may offer a more realistic platform to study oral carcinogenesis. In this perspective, we also discuss our preclinical studies to demonstrate the potential of black raspberry extracts on the prevention of OSCC. Specifically, we were the first to demonstrate that black raspberry inhibited DB[a,l]P-DNA binding and of particular importance its capacity to enhance the repair of DB[a,l]P-induced bulky lesions in DNA. We believe that the information presented in this perspective will stimulate further research on the impact of environmental carcinogens in the development of oral cancer and may lead to novel strategies toward the control and prevention of this disease.

Mouse Tumor-Bearing Models as Preclinical Study Platforms for Oral Squamous Cell Carcinoma

“…However, as a novel and promising model, there are still several barriers to the full application of GEMMs. Firstly, although the introduction of mice expressing Cre recombinase is driven by oral mucosa-specific promoters such as K5 or K14, the tumors generated by GEMMs have low specificity and appear in sites other than the oral cavity, such as the skin, tongue, esophagus, and forestomach (180,181,185,186). Secondly, because of the full range of genetic changes caused by gene editing, GEMMs have a short lifespan and a high mortality rate, and highly malignant OSCC may not develop.…”

Effects of chronic alcohol consumption on DNA damage and immune regulation induced by the environmental pollutant dibenzo[a,l]pyrene in oral tissues of mice

“…Head and neck squamous cell carcinoma (HNSCC), the vast majority of which occurs in the oral cavity, is the sixth most common malignancy worldwide, representing a major international health problem (1). HNSCC is the most traumatic form of malignancy due to its visible distortion of the face, and disruption of breathing, speaking and swallowing (2).…”

“…Epidemiological data strongly support the role of exogenous factors such as tobacco, alcohol and human papilloma virus infection as causative factors; other factors (betel quid chewing, smokeless tobacco, marijuana, and certain dietary components) have also been implicated in the development of HNSCC (1). A recent study found that alcohol consumption combined with tobacco smoking results in a supra-multiplicative synergistic effect which enhances cancer risk up to 14-fold (5).…”

“…PAHs are formed in tobacco smoke and through other environment combustion sources and are thought to play an important role in cancer development at numerous sites including lung and oral cavity (1). Our previous studies showed that both dibenzo[ a,l ]pyrene (DB[ a,l ]P), a representative example of PAHs, and its diol epoxide (DB[ a,l ]PDE) induced SCC in the oral tissues of mice in a dose-dependent manner.…”

Lugol Iodine Staining Test in Assessing Disease Free Margins in Tonsillar Cancer

“…The carcinoma of the tonsil represents 10-15% of total malignant tumors in the oral cavity, have a predilection for male (4:1 is the male: female ratio) especially between the 6 th -8 th decade of life and the great majority is represented by squamous cell carcinomas [1,4]. These patients often present a history of alcohol and tobacco abuse, human papilloma virus [5][6][7][8]. Due to the lack of symptoms in the early stages of the disease the patients report to medical examination late, in advanced stages, when the prognosis is poor despite multimodal oncologic treatment (surgery, radiotherapy, chemotherapy).…”