Masato Hirano

Solitary fibrous tumor in the mental region

Solitary fibrous tumor (SFT) is a rare, benign, soft tissue tumor that most commonly occurs in the pleura; however, it has recently been described in other sites of the body. To date, eight examples of oral SFT have been reported. This paper is a description of the first case of an SFT occurring as a soft tissue tumor in the mental region. Histologically, the tumor was composed predominantly of rather uniform spindle‐shaped fibroblastic cells arranged in vague fascicles or in a haphazard fashion, intermingled with abundant collagen fibers. Immunohistochemically, the tumor cells were positive for CD34 and vimentin, and weakly positive for muscle actin and α‐smooth muscle actin. The diagnosis of SFT may be difficult as this tumor shares a number of histological features with other soft tissue tumors. Awareness of its occurrence in the oral cavity is important so that confusion with other spindle cell neoplasms can be avoided.

Expressions of junB and c‐fos are enhanced in 4‐nitroquinoline 1‐oxide‐induced rat tongue cancers

Activator protein‐1 (AP‐1) is a transcription factor activated in many tumors. Using 4‐nitroquinoline 1‐oxide (4NQO)‐induced rat tongue cancers (TC), the present study investigated the expression levels of genes that encode the components of AP‐1, the jun gene family (c‐jun, junB and junD) and the fos gene family (c‐fos, fra‐1, fra‐2 and fosB). Expression levels of junB and c‐fos mRNAs in TC were significantly elevated compared with those in epithelial tissue of control rat tongue, although only c‐fos mRNA levels tended to be elevated in dysplastic tongue epithelium. Histologically, all 4NQO‐induced rat TC were well‐differentiated squamous cell carcinomas. Immunostaining for JunB and c‐Fos proteins was positive in the nuclei of tumor cells of all TC. It is noteworthy that JunB was negative, but c‐Fos was positive in the dysplastic tongue epithelium of the 4NQO‐treated rats. Immunostaining for both proteins was negative in tongue mucosal epithelium of control rats. There were no mutations in the coding regions of either junB or c‐fos in all the TC examined. These results suggest the possibility that the expressions of junB and c‐fos were enhanced stepwise in 4NQO‐induced carcinogenesis of rat tongue, and that the coexpression of JunB and c‐Fos might play an important role in the establishment of TC.

Five Quantitative Trait Loci Affecting 4‐Nitroquinoline 1‐Oxide‐induced Tongue Cancer in the Rat

In our previous study, Dark‐Agouti (DA) rats were found to be highly susceptible to 4‐nitroquino‐line 1‐oxide (4NQO)‐induced tongue carcinoma (TC), whereas Wistar/Furth (WF) rats were barely susceptible. Interval mapping analysis of reciprocal backcross rats showed two quantitative trait loci (QTL) on rat chromosomes (RNO) 1 and 19. In the present study, a composite interval mapping analysis was applied to 4NQO‐induced TC in 130 (DAxWF) F2 rats, demonstrating five independent QTL, Tongue squamous cell carcinoma 1‐5 (Tscc1‐5), responsible for phenotypic differences in the size and number of TCs in the two strains. Two of these QTL were mapped on RNO1, and the others were mapped on RNO4, 14, and 19. The DA allele at these loci consistently yielded semidominant susceptibility to TC. Out of the five loci detected in this F2 generation, Tscc1 and 2 were identical to Stcl and Rtc1 described in our previous study, but the other three were novel. We propose a new nomenclature consistent with their function. Genome‐wide screening of the F2 progeny also suggested the presence of three additional QTL on RNO5, 6, and 10. The possible roles of these loci in tongue carcinogenesis are discussed.

CARCINOGENESIS MODIFIER LOCI IN RAT TONGUE ARE SUBJECT TO FREQUENT LOSS OF HETEROZYGOSITY

Rats of the DA strain are highly susceptible to 4NQO‐induced TCs, whereas WF rats are barely susceptible. In (DA × WF)F2 rats, 5 QTL, Tscc1–5, are responsible for most of the phenotypic variations, though they do not account for all of the phenotypic differences between WF and DA rats. Analysis of 40 tongue tumors >5 mm in diameter from (DA × WF)F1 rats for LOH at the Tscc loci revealed a high frequency of LOH in chromosomal regions where the Tscc2, ‐3 and ‐4 loci map. In most cases of LOH, the allele of the barely susceptible WF strain was lost, suggesting that these loci in the WF strain encode tumor‐suppressor genes. Analysis of the same tumors for somatic mutations in oncogenes indicated frequent alteration of Ha‐ras, which maps in the Tscc3 region, but rare mutation of the p15INK4B and p16INK4A genes or the p53 and Msh2 genes. Frequent LOH was also found on rat chromosomes 5 (RNO5) and 6 (RNO6). Tumors of large size accumulated LOH at multiple loci, suggesting the involvement of Tscc loci in tumor progression.

Genetic Predisposition to 4NQO-Induced Tongue Carcinogenesis in the Rat

Objective: This study aims to elucidate the genetic basis of predisposition to 4-nitroquinoline 1-oxide (4NQO)-induced tongue cancers (TCs). Materials and Methods: We have reported that inbred Dark-Agouti (DA) strain rats were highly susceptible to 4NQO-induced TCs, whereas Wistar/Furth (WF) rats were resistant to tongue squamous cell carcinomas induced by oral administration of 4NQO. Using size and number of the tumours as quantitative parameters, responsible host loci were analysed by an interval mapping of F2 intercross of DA and WF given carcinogenic regimen. Also, loss of heterozygosity (LOH) at these loci was analysed in tongue cancers in (DA × WF) F1. Results: We identified and mapped 5 significant quantitative trait loci (QTL), the Tongue squamous cell carcinoma 1–5 (Tscc1–5), and several other suggestive QTL that determine susceptibility to 4NQO-induced TC. Study of TCs induced in (DA × WF)F1 rats revealed a high frequency of LOH in the chromosomal regions of Tscc2, 3, and 4 and also of suggestive QTL on chromosomes 5 and 6. The fact that LOH was found only in larger TCs indicates that LOH occurred in the process of tumour progression. In most LOH, the allele of the resistant WF strain was lost, suggesting that these loci may encode tumour suppressor genes. In larger TCs, in addition to LOH, point mutations and the methylation of possible candidate genes were accumulated. Conclusion: These observations indicate that the 4NQO-induced TC in the rat is a multifactorial disease of a polygenic trait. This model will be useful to understand the complicated genetic basis of predisposition to oral cancers.