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Direct progression of capsular invasive carcinomas from subcapsular focal hyperplasias induced by hypothyroidism-mediated tumor promotion in a rat two-stage thyroid carcinogenesis model

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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.


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.


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.


Subcapsular FFCH-forming cells can potentially spread directly into the fibrously thickened capsule to form CICs by accelerating cell-cycle activity.

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We thank Mrs. Shigeko Suzuki for her technical assistance in preparing histological specimens.

Conflict of interest

All authors disclose that there are no conflicts of interest that could inappropriately influence the outcome of the present study.

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Correspondence to Makoto Shibutani.

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Ago, K., Kemmochi, S., Morita, R. et al. Direct progression of capsular invasive carcinomas from subcapsular focal hyperplasias induced by hypothyroidism-mediated tumor promotion in a rat two-stage thyroid carcinogenesis model. J Cancer Res Clin Oncol 139, 395–401 (2013). https://doi.org/10.1007/s00432-012-1338-4

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  • Rat thyroid carcinogenesis
  • Capsular invasive carcinoma
  • Cell cycle
  • Cell proliferation
  • Tenascin-C