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.