title: Development of invasive follicular cell carcinomas in a rat thyroid carcinogenesis model: biological impact of capsular inflammation and reduced cyclooxygenase-2 expression.
abstract: We have previously reported that thyroid capsular inflammation induced by sulfadimethoxine (SDM), a goitrogen, might play a role in development of invasive follicular cell adenocarcinomas in rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). The present study was designed to examine the role of cyclooxygenase (COX)-2, widely known to be up-regulated in inflammatory states, during chemically induced rat thyroid carcinogenesis. Male F344 rats received a subcutaneous DHPN (2800 mg/kg) injection, and 1 week later were allowed free access to drinking water containing antithyroidal propylthiouracil (PTU, 0.003%) or SDM (0.1%) for 4 or 10 weeks. Control groups receiving goitrogen alone and no treatment were also included. At week 4, diffuse follicular cell hyperplasia was induced in all PTU- and SDM-treated groups, along with fibrous capsular thickening and capsular thickening with inflammation, respectively. Additionally, multiple focal follicular cell hyperplasias and adenomas were observed in the DHPN + PTU and DHPN + SDM cases. At week 10, adenocarcinomas invasive to the capsule and restricted to the capsular adjacent region, were frequent in the DHPN + SDM group, but not observed in the animals given DHPN + PTU. Western blots and immunohistochemistry revealed constitutive COX-2 expression in non-neoplastic follicular cells of the control and all of the PTU- and SDM-treated rats. However, COX-2 reactivity was significantly reduced or negative in the preneoplastic/neoplastic lesions in the DHPN-treated groups. In fibrous or inflamed thickened capsules, only a few component cells with inflammatory elements were positive for COX-2, and there was no significant difference in this regard between the PTU and SDM treatments. The present results suggest that capsular inflammation could play a role in development of invasive carcinomas, but COX-2 expression does not make a major contribution.
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: Mai
authors.initials: M
authors.lastname: Hasumura
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Onose
authors.forename: Makoto
authors.initials: M
authors.lastname: Ueda
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Takizawa
authors.forename: Young-Man
authors.initials: YM
authors.lastname: Cho
authors.forename: Masao
authors.initials: M
authors.lastname: Hirose
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000139:chemically induced / Q000473:pathology*; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D013956:Antithyroid Agents / Q000494:pharmacology; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology*; D007453:Iodide Peroxidase / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009602:Nitrosamines / Q000633:toxicity; D011441:Propylthiouracil / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013412:Sulfadimethoxine / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000139:chemically induced / Q000473:pathology*
chemical_list: D000890:Anti-Infective Agents; D013956:Antithyroid Agents; D002273:Carcinogens; D004791:Enzyme Inhibitors; D009602:Nitrosamines; D013412:Sulfadimethoxine; C012457:diisopropanolnitrosamine; D011441:Propylthiouracil; D007453:Iodide Peroxidase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases