Apc-Mutant Kyoto Apc Delta (KAD) Rats Are Susceptible to 4-NQO-Induced Tongue Carcinogenesis

Masahito Shimizu,Kazuto Yoshimi,Naoki Watanabe,Tadao Serikawa,Takafumi Naiki,Yohei Shirakami,Takahiro Kochi,Takayuki Mori,Hisataka Moriwaki,Takashi Kuramoto,Takuji Tanaka

doi:10.3390/cancers6031522

Masahito Shimizu, Kazuto Yoshimi + Show 9 more

Open Access

https://doi.org/10.3390/cancers6031522

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Journal: Cancers	Publication Date: Jul 21, 2014
Citations: 52	License type: CC BY 4.0

Affiliation: Gifu University, Kyoto University, Gifu Municipal Hospital

Abstract

Despite widening interest in the possible association between infection/inflammation and cancer development, knowledge of this issue in relation to oral cancer remains inadequate. This study aimed to determine the susceptibility of Apc-mutant Kyoto Apc Delta (KAD) rats, which are vulnerable to developing inflammation-associated colorectal carcinogenesis, to 4-nitroquinoline 1-oxide (4-NQO)-induced tongue carcinogenesis in order to clarify the role of inflammation in oral cancer. KAD (20 males and 22 females) and F344/NS1c (22 males and 23 females) rats received drinking water with or without 4-NQO (20 ppm) for eight weeks. Histopathological and immunohistochemical analyses of the tongue were performed at week 20. Additionally, the mRNA expression of inflammatory cytokines in the tongue mucosa was determined at week 8. Tongue squamous cell carcinoma (SCC) developed in the KAD and F344/NS1c rats that received 4-NQO. Regardless of gender, the incidence and multiplicity of tongue SCC were greater in the KAD rats than in the F344/NS1c rats. In addition, the multiplicity of tongue SCC in the female KAD rats was significantly greater than that observed in the male KAD (p < 0.01) and female F344/NS1c rats (p < 0.05). The levels of inflammation and the mRNA expression of inflammatory cytokines in the tongue in the 4-NQO-treated female KAD rats were the highest among the rats given 4-NQO. These results show that KAD rats, particularly females, are susceptible to 4-NQO-induced tongue carcinogenesis, suggesting the utility of models employing KAD rats for investigating the pathobiology of oral (tongue) carcinogenesis associated with inflammation.

Highlights

Half of all causes of head and neck squamous cell carcinoma, which represents the fifth most frequent cancer worldwide, are located in the oral cavity
The multiplicity of tongue squamous cell carcinoma (SCC) in the Kyoto Apc Delta (KAD) rats of either sex (1.93 ± 0.92 in males and 2.69 ± 1.49 in females) was greater than that observed in the F344/NS1c rats (1.07 ± 1.21 in males and 1.33 ± 1.29 in females), while the values noted in the female KAD rats were significantly higher than those observed in the female F344/NS1c rats (p < 0.05)
The multiplicity of tongue SCC of female KAD rats was significantly higher than that observed in the male KAD rats (p < 0.01)

Summary

Introduction

Half of all causes of head and neck squamous cell carcinoma, which represents the fifth most frequent cancer worldwide, are located in the oral cavity. Since the oral cavity is constantly exposed to environmental substances, including certain carcinogens, the tissue is frequently under inflammatory stress and vulnerable to various infections causing infection/inflammation-related diseases, including cancer [2]. Malignant neoplasms are frequently surrounded by an inflammatory microenvironment rich in inflammatory cytokines, growth factors and chemokines, which promote malignant cell growth [5,6]. These factors are produced by the tumor itself and its surrounding tissue, and contribute to the progression of malignancy [7]

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