title: Direct progression of capsular invasive carcinomas from subcapsular focal hyperplasias induced by hypothyroidism-mediated tumor promotion in a rat two-stage thyroid carcinogenesis model.
abstract: OBJECTIVE
  Some goitrogens promote thyroid carcinogenesis in rats in an initiation-promotion model; this model frequently produces carcinomas that invade fibrously thickened capsules, termed capsular invasive carcinomas (CICs). The present study tested a hypothesis that CICs originate from parenchymal proliferative lesions located beneath the capsule.
  
  
  METHODS
  Cell proliferation activity, cell-cycle kinetics and cellular invasion were immunohistochemically examined in subcapsular proliferative lesions in male F344 rats treated with an anti-thyroid agent, propylthiouracil or sulfadimethoxine, during the tumor-promotion phase after initiation with N-bis(2-hydroxypropyl)nitrosamine.
  
  
  RESULTS
  Focal follicular cell hyperplasias (FFCHs) were the most commonly observed parenchymal proliferative lesions. Subcapsular FFCHs located near CICs showed more Ki-67(+) cells in the capsular side than the contrary parenchymal center side. Most of these FFCHs located near CICs showed accumulated immunoreactivity for cyclin A, cyclin D, cyclin E and cyclin-dependent kinase-2, whereas most subcapsular FFCHs located elsewhere did not show such accumulated expression of cell-cycle molecules. Subcapsular FFCHs immunoreactive at the capsular front for tenascin-C, a tumor invasion marker of extracellular matrix protein, showed high proliferation activity.
  
  
  CONCLUSIONS
  Subcapsular FFCH-forming cells can potentially spread directly into the fibrously thickened capsule to form CICs by accelerating cell-cycle activity.
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Ago
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kemmochi
authors.forename: Reiko
authors.initials: R
authors.lastname: Morita
authors.forename: Atsunori
authors.initials: A
authors.lastname: Yafune
authors.forename: Ayako
authors.initials: A
authors.lastname: Shiraki
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Mitsumori
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
mesh_terms: D000818:Animals; D002273:Carcinogens; D002277:Carcinoma / Q000139:chemically induced / Q000209:etiology / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D006965:Hyperplasia / Q000209:etiology / Q000473:pathology; D007037:Hypothyroidism / Q000150:complications* / Q000473:pathology; D008297:Male; D009361:Neoplasm Invasiveness; D009602:Nitrosamines; D051381:Rats; D011916:Rats, Inbred F344; D013961:Thyroid Gland / Q000473:pathology*; D013964:Thyroid Neoplasms / Q000139:chemically induced / Q000209:etiology / Q000473:pathology*
chemical_list: D002273:Carcinogens; D009602:Nitrosamines; C012457:diisopropanolnitrosamine