Abstract
Oral squamous cell carcinoma is one of the most common human neoplasms, and prevention of this malignancy requires a better understanding of its carcinogenesis process. To this end, we tried to establish an animal model using the human c-Ha-ras proto-oncogene-carrying transgenic (Tg) rats and the carcinogen 4-nitroquinoline 1-oxide (4-NQO). 4-NQO (20 p.p.m.) was administered to Tg and non-Tg rats for 8 weeks in their drinking water, and then the occurrence of tongue carcinogenesis was compared during the experimental period of 22 weeks. In addition, we determined the DNA ploidy in tongue lesions and examined the immunohistochemical expression of five biomarkers such as cyclin D1, glutathione S-transferase placental form, cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) and beta-catenin. Next, the cancer chemopreventive effects of nimesulide, pioglitazone and a synthetic geranylated derivative, which have been reported to be inhibitors of tongue carcinogenesis, were examined in Tg rats treated with 4-NQO. Either during or after treatment with 4-NQO in the drinking water, tongue dysplasia and tumors were observed on the tongues of both Tg and non-Tg rats, with a greater incidence and multiplicity in Tg rats. Histopathologically, squamous cell dysplasia, papilloma and carcinoma with or without invasion were present in the tongue. Immunohistochemistry revealed that expression levels against five biomarkers increase with disease progression, and the changes correlated with those of the DNA ploidy pattern. Interestingly, a strong expression of COX-2, iNOS and beta-catenin was observed on the invasive front of squamous cell carcinomas. A subsequent chemoprevention study using Tg rats showed that the chemicals tested suppressed the occurrence of tongue carcinomas when they were administered after 4-NQO-exposure. These results may thus indicate that our 4-NQO-induced Tg rat tongue carcinogenesis model simulates many aspects of human oral carcinogenesis and it can be applied for an analysis of oral cancer development while also helping to identify potentially effective cancer chemopreventive agents against oral cancer.
Highlights
Oral cancer, mostly squamous cell carcinoma (SCC), is considered to be one of the most common neoplasms in the world with nearly 390 000 new cases per year [1]
When they were administered after 4-nitroquinoline 1-oxide (4-NQO)-exposure. These results may indicate that our 4-NQO-induced Tg rat tongue carcinogenesis model simulates many aspects of human oral carcinogenesis and it can be applied for an analysis of oral cancer development while helping to identify potentially effective cancer chemopreventive agents against oral cancer
Human c-Ha-ras proto-oncogene Tg and non-Tg rats bred by CLEA Japan (Tokyo, Japan) [35] at 6 weeks of age were obtained and maintained in plastic cages in an experimental room controlled at 23 Æ 2C temperature, 50 Æ 10% humidity and lighting (12 h light–dark cycle)
Summary
Mostly squamous cell carcinoma (SCC), is considered to be one of the most common neoplasms in the world with nearly 390 000 new cases per year [1]. This malignancy is common in such developing countries as India, Sri Lanka, Vietnam, the Philippines and Brazil, where it constitutes up to 25% of all types of cancers [2]. Many patients tend to develop secondary primary tumors even if the primary tumors can be treated [6] This suggests the occurrence of a multi-focal tumor development, called ‘field cancerization’ [7]. The development of cancer chemoprevention is an important strategy for fighting this malignancy [8,9,10], and an animal model for preclinical studies is warranted to clarify how best to control this epithelial malignancy
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