title: Sequential analysis of development of invasive thyroid follicular cell carcinomas in inflamed capsular regions of rats treated with sulfadimethoxine after N-bis(2-hydroxypropyl)nitrosamine-initiation.
abstract: A 2-stage thyroid follicular carcinogenesis model in rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN) is widely used to detect modifying effects of chemicals on thyroid carcinogenesis. A number of goitrogens are known to strongly promote carcinogenesis, and the carcinomas often originate adjacent to the thyroid capsule and show invasive growth into the capsule or adjacent tissues. To clarify mechanisms of progression to invasive carcinomas, we sequentially evaluated histopathological and immunohistochemical characteristics of thyroids in male F344 rats treated with sulfadimethoxine (SDM, 0.1% in drinking water) for 0-10 weeks beginning 1 week after DHPN initiation (2800 mg/kg body weight, single s.c. injection). In DHPN-SDM-treated rats, multiple focal hyperplasias and adenomas developed in thyroid follicular parenchyma at weeks 4 to 6. Apart from the proliferative lesions, capsular thickening with inflammatory cell infiltration, mainly consisting of macrophages, and migration of follicular epithelium into the capsule were also observed. Focal hyperplasias/adenomas adjacent to the capsule progressively developed to invasive carcinomas at weeks 6 to 10. In thyroid parenchyma, malignant lesions were seldom observed. With SDM-treatment alone, although no neoplastic lesions were observed, capsular thickening with inflammation and epithelial migration resulted in intracapsular residual follicles. Intracapsular residual follicular cells as well as invasive and intrathyroidal carcinoma cells generally showed increased cell proliferative activity, coincidental with cytoplasmic/nuclear positivity for beta-catenin. These results suggested that beta-catenin activation related to capsular inflammation may play a role in development of invasive carcinomas but is insufficient for tumor formation by itself. Whether this is associated with mutations in the beta-catenin gene remains to be clarified.
authors.affiliation: Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-Ku, Tokyo 158-8501, Japan. imai@nihs.go.jp
authors.forename: Toshio
authors.initials: T
authors.lastname: Imai
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Onose
authors.forename: Mai
authors.initials: M
authors.lastname: Hasumura
authors.forename: Makoto
authors.initials: M
authors.lastname: Ueda
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Takizawa
authors.forename: Masao
authors.initials: M
authors.lastname: Hirose
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000139:chemically induced / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D014408:Biomarkers, Tumor; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004359:Drug Therapy, Combination; D006965:Hyperplasia; D007279:Injections, Subcutaneous; D008297:Male; D009361:Neoplasm Invasiveness; D009602:Nitrosamines / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013412:Sulfadimethoxine / Q000008:administration & dosage / Q000633:toxicity*; D013961:Thyroid Gland / Q000187:drug effects* / Q000473:pathology; D013964:Thyroid Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism; D014881:Water Supply; D051176:beta Catenin
chemical_list: D014408:Biomarkers, Tumor; D002273:Carcinogens; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D009602:Nitrosamines; D015534:Trans-Activators; D051176:beta Catenin; D013412:Sulfadimethoxine; C012457:diisopropanolnitrosamine