thiouracil and Cell-Transformation--Neoplastic

To investigate the cell cycle kinetics during the tumor promotion process induced by hypothyroidism in a rat model of thyroid follicular cell carcinogenesis, immunohistochemical analysis of cell cycle molecules and related signaling molecules was performed in conjunction with analysis of cell proliferation activity in an initiation-promotion model. Male F344 rats were injected with N-bis(2-hydroxypropyl)nitrosamine, and one week later treated with 6-propyl-2-thiouracil (PTU) at 12ppm in the drinking water for 4, 10 or 15 weeks. At each time point, proliferative lesions increased the expression of cyclin A, cyclin D, cyclin E and cyclin-dependent kinase (Cdk)-2, in association with the development of lesion stages from the early focal hyperplasia to the late carcinoma, while a subpopulation of proliferative lesions showed decreased numbers of both cell division cycle-2- and Ki-67-positive cells at week 15 compared with that at week 10, suggesting a reduced promoting effect of serum thyroid-stimulating hormone in the sensitive cellular population after long-term exposure to PTU. On the other hand, increased immunolocalization of phosphorylated and inactive glycogen synthase kinase (GSK)-3beta was observed in a subpopulation of proliferative lesions, in parallel with the cyclins and Cdk2. Nuclear immunoreactivity of phosphorylated and inactive retinoblastoma (Rb) protein was also increased in association with lesion development, with carcinomas showing increased cytoplasmic localization. The results suggest that proliferative lesions activate the cell cycle machinery following tumor promotion via a regulatory mechanism involving inactivation of GSK3beta and Rb protein, the latter signaling mechanism involving its aberrant nucleocytoplasmic transport for the acquisition of a malignant phenotype.

Topics: Adenocarcinoma, Follicular; Adenoma; Animals; Carcinogens; Cell Cycle Proteins; Cell Nucleus; Cell Transformation, Neoplastic; Cytoplasm; Disease Models, Animal; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Immunohistochemistry; Male; Nitrosamines; Protein Transport; Rats; Rats, Inbred F344; Retinoblastoma Protein; Signal Transduction; Thiouracil; Thyroid Neoplasms

Transplantable tumours were induced in the thyroids of Fischer 344 rats fed thiouracil (TU) in a moderately low iodine diet for 8-13 months. Pieces of hyperplastic thyroid were implanted subcutaneously into rats fed a TU containing diet. Almost all implants gave rise to very small vascularized transplants but there were three significantly larger, pieces of which were transplanted again and gave rise to the tumour lines. From the third transplantation generation on, pieces of tumours were implanted into rats treated to have elevated circulating thyrotropin and a group fed a high iodine diet. With some exceptions, the implants grew only in rats fed the TU or a low iodine diet and yielded TSH-dependent tumours. Almost all the tumours observed initially were papillary, and most of the remainder had colloid-filled follicles bounded by columnar cells. One line of tumours was of the latter type for eight generations. The others had more complex histories, in which there were sublines that were papillary for eight or nine generations, whereas, others became progressively more cellular or follicular, and more heterogeneous with respect to histological types present per section at rates that varied with the subline. The large number of population doublings necessary to make a one gram tumour from a single original tumour cell indicates that the cells of dependent papillary tumours were immortalized.

Topics: Animals; Carcinogens; Cell Transformation, Neoplastic; Female; Hyperplasia; Male; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Neovascularization, Pathologic; Pedigree; Rats; Rats, Inbred F344; Thiouracil; Thyroid Gland; Thyroid Neoplasms; Thyrotropin

Topics: Adenoviridae; Animals; Autoradiography; Azaguanine; Carcinoma, Squamous Cell; Cell Fusion; Cell Line; Cell Transformation, Neoplastic; Cricetinae; Dactinomycin; Deoxyuridine; Inclusion Bodies, Viral; Laryngeal Neoplasms; Mitomycins; Parainfluenza Virus 1, Human; Phenylalanine; Puromycin; Thiouracil; Thymidine; Tritium; Virus Replication

Topics: Animals; Antimetabolites; Azaguanine; Cell Line; Cell Transformation, Neoplastic; Dactinomycin; Fibroblasts; Haplorhini; Idoxuridine; In Vitro Techniques; Kidney; Mice; Mitomycins; Phenylalanine; Puromycin; Simian virus 40; Thiouracil

Topics: Aging; Animals; Carcinogenesis; Cell Transformation, Neoplastic; Neoplasms; Rats; Thiouracil; Thyroid Gland; Thyroid Neoplasms