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 β-catenin. These results suggested that β-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 β-catenin gene remains to be clarified.

Depression of T cell‐mediated immunity reduces sulfadimethoxine‐induced capsular inflammation and inhibits associated development of invasive thyroid follicular cell carcinomas in rats

“…(19,20) The reason for the lack of any capsular inflammatory reaction in the present study at this stage is not clear. At week 10, however, relative thyroid weights reached around 50 mg/ 100 g bodyweight in both the rnu/rnu and rnu/+ groups, but major inflammation was only observed in the rnu/+ group.…”

“…Preneoplastic and neoplastic lesions of follicular epithelial cells were classified in H&E-stained sections, as described earlier. (19,20) Immunohistochemical staining. Anti-rat CD8a antibody for Tcell surface antigen (clone OX-8) and anti-rat CD45R antibody for B-cell surface antigen (clone HIS24) were purchased from BD Biosciences (San Jose, CA, USA).…”

“…Although the cause of the capsular inflammation is yet to be clarified, lesions induced by SDM treatment alone are composed of large numbers of macrophages and lymphocytes as well as fibroblasts. (19) In the literature, induction of intrathyroidal T cell-mediated autoimmune reactivity in rats by a combined antithyroidal treatment with an iodine-deficient diet and perchlorate has been reported.…”

“…Although the cause of the capsular inflammation is yet to be clarified, lesions induced by SDM treatment alone are composed of large numbers of macrophages and lymphocytes as well as fibroblasts. (19) In the literature, induction of intrathyroidal T cell-mediated autoimmune reactivity in rats by a combined antithyroidal treatment with an iodine-deficient diet and perchlorate has been reported. (21) Thus we hypothesized that an unusual immunogenic response via T-cell recognition, with respect to goiter and enhancement of inflammation by interplay between T cells and macrophages, occurs during thyroid carcinogenesis in our DHPN-SDM rat model.…”

“…(17,18) We previously reported rapid induction of invasive follicular cell carcinomas in thickened thyroid capsules with inflammation in a rat two-stage carcinogenesis model by treatment with the antithyroidal agent sulfadimethoxine (SDM) after single injection of the genotoxic thyroid carcinogen N-bis(2-hydroxypropyl)-nitrosamine (DHPN). (19,20) Thus, thyroid capsular inflammatory lesions may play an important role in the development of invasive carcinomas in rats. Although the cause of the capsular inflammation is yet to be clarified, lesions induced by SDM treatment alone are composed of large numbers of macrophages and lymphocytes as well as fibroblasts.…”