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

Abstract

We previously demonstrated that thyroid capsular inflammation induced by continuous treatment with the antithyroidal agent sulfadimethoxine is associated with development of invasive follicular cell carcinomas in rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). The inflammatory changes are characterized by large numbers of macrophages and lymphocytes as well as fibroblasts and we hypothesized that it might be enhanced by interplay between macrophages and T cells. To clarify this hypothesis, a comparative study was conducted between athymic nude (rnu/rnu) rats and euthymic (rnu/+) littermates initiated with DHPN (2800 mg/kg, s.c.) followed by sulfadimethoxine treatment in drinking water (0.1%) for 10 weeks. In rnu/+rats, marked capsular thickening with inflammation was induced along with invasive follicular cell carcinomas (2.8 ± ± ± ± 1.3/rat). In rnu/rnu rats, limited fibrous capsular thickening was noted with or without minimal inflammatory change, and the multiplicity of invasive carcinomas was significantly lower (1.1 ± ± ± ± 1.0/ rat, P < 0. I t is generally accepted that inflammation is an immune reaction not only to exogenous but also to mutated or overexpressed endogenous proteins. It has both advantages and disadvantages for humans and animals. For example, the immune system recognizes and eliminates tumor cells because of their expression of tumor-associated antigens (e.g. HER-2/neu in breast carcinomas)(1) but chronic inflammation resulting in enhanced epithelial cell turn over may be a major contributor to carcinogenesis.(2) Furthermore, neoplastic transformation and progression is associated with the release of highly reactive oxygen and nitrogen species (RONS) from inflammatory cells.(3) Hydrogen peroxide, nitric oxide (NO) or other RONS can damage DNA via several mechanisms, and NO is recognized to stimulate proinflammatory cytokines as well as cyclooxygense-2 (COX-2) activity, leading to tumor growth via enhanced prostaglandin production and inactivation of p53-mediated caspase.(4) Increased expression of inducible nitric oxide synthase (iNOS) or COX-2 in tumor epithelial cells as well as stromal inflammatory cells has been demonstrated in human gastric, (5) colon, (6,7) breast (8) and hepatic (9) tumors, and their contribution to tumor development and progression is now generally accepted. Overexpression of iNOS and COX-2 has also been reported in azoxymethane-induced colon, (10) 7,12-dimethylbenz(a)anthracene-induced mammary,choline-deficient, l-amino acid-defined diet-caused hepatocellular,and indium-phosphate-induced lung (13) carcinogenesis in rats. Monocytes, macrophages and neutrophils produce iNOS in inflammatory states (14) in response to cytokines such as interferon (IFN)-γ.(15) Th1 and CD8 + T cells are major sources of IFN-γ during immunoresponses, (16) and activated macrophages also secrete cytokines like interleukin (IL)-12, which in turn stimulate Th1-type T cells to secrete IFN-γ and IL-2, activating other resting macrophages in an upward spiral. (17,18) We previously...

Inhibitory effects of aminoguanidine on thyroid follicular carcinoma development in inflamed capsular regions of rats treated with sulfadimethoxine after N‐bis(2‐hydroxypropyl)nitrosamine‐initiation

“…Migration of follicular epithelium from disrupted follicles into capsules was demonstrated at 4–6 weeks after the start of SDM treatment in rats initiated with DHPN in our previous experiments conducted under the same protocol as the present one, but their biological significance is uncertain. ( 13,14,25 ) Again in the present study, migrating cells were frequently observed, but they appeared to lack iNOS expression. On the other hand, immunoreactivity for iNOS was observed in carcinoma cells in invasive carcinomas, in which diffuse nuclear positivity for ssDNA was also demonstrated.…”

“…(19) In addition, follicular carcinomas were discriminated as intrathyroidal and invasive carcinomas involving the thyroid capsular and/or extrathyroidal tissues. (14) Immunohistochemical staining. Anti-rat CD3 antibody for T-cell surface antigen (clone G4.18, diluted at 1/500) and anti-mouse iNOS (clone 6, 1/200) were purchased from BD Biosciences (San Jose, CA, USA).…”

“…( 19 ) In addition, follicular carcinomas were discriminated as intrathyroidal and invasive carcinomas involving the thyroid capsular and/or extrathyroidal tissues. ( 14 )…”

Involvement of PTEN/Akt signaling in capsular invasive carcinomas developed in a rat two-stage thyroid carcinogenesis model after promotion with sulfadimethoxine

“…Promotion with propylthiouracil, another anti-thyroid agent that is less potent for inducing capsular inXammation than SDM, produces less frequent capsular invasive tumors, in parallel with weak capsular inXammation and Wbrosis (Imai et al 2005). Imai et al (2007) suggested that development of invasive carcinomas in the present model is enhanced by capsular inXammation mediated by T cells, and inducible nitric oxide synthase induction in the inXamed lesions may play a role in tumor progression. Thus, although neoplastic cell invasion itself can trigger Wbrous reactions, Wbrotic tissue formed during the capsular inXammation may provide the place of neoplastic cell invasion in response to inXammatory reactions.…”

“…Rats were given a single injection of the thyroid carcinogen, N-bis(2-hydroxypropyl) nitrosamine (DHPN), and then treated with an anti-thyroid agent, sulfadimethoxine (SDM), during the promotion stage. Although the role of inXammatory cell responses in capsular invasion was investigated in this model (Imai et al 2005(Imai et al , 2007, cellular signaling in the neoplastic cells responsible for this invasion was not.…”