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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies on thyroid tumorigenesis in rodents have explored the role of oncogene mutation in tumour development. However, many mutagens are also known to decrease DNA methylation, another factor known to be important in the regulation of gene expression. We report the results of a small study to examine whether the demethylating agents 5-azacytidine and 5-aza-2-deoxycytidine could promote radiation- or goitrogen-induced tumorigenesis in the mouse, and whether they could potentiate the effect of a combined radiation and goitrogen regime. Three single doses of either 5-azacytidine or 5-aza-2-deoxycytidine increased the frequency of lesions in the goitrogen-treated animals; one of these lesions was a metastasising carcinoma. Thyroid carcinomas are very rare in mice in the absence of mutagen treatment, and metastasis is particularly unusual. There was no significant difference, at the dosages used, between the number of tumours induced by demethylating agents and those induced by a mutagen (radiation) in goitrogen-treated animals. Unlike goitrogens, demethylating agents did not promote radiation-induced tumorigenesis, and they did not produce any significant potentiation of the conventional regime of radiation and goitrogen at the dosages used. This study suggests that the role of non-genotoxic factors, such as agents affecting patterns of DNA methylation, warrants consideration in thyroid tumorigenesis.
Carcinogenesis 1992 Jun
PMID:Production of thyroid tumours in mice by demethylating agents. 137 18

The National Toxicology Program data base on 343 mouse and rat carcinogenesis studies was reviewed to determine the frequency of and relationship between hyperplastic and neoplastic follicular lesions of the thyroid gland. The frequency of chemically related lesions in the thyroid was also compared to neoplastic lesions in the liver to investigate a possible correlation. The percentage of studies observed to have positive or equivocal chemically related thyroid proliferative lesions was rats: male, 14%, female, 11%; mice; male, 8%; female, 9%. When positive in one sex for a given chemical, there was a 60-80% chance of it being positive in the other sex of the same species, although interspecies correlation was not as strong. Thyroid follicular cell neoplasia without hyperplasia was uncommon in mice but was common in rats. Chemicals that caused thyroid proliferative changes were more likely (P less than 0.05) to produce liver neoplasms (both within and between species) than were chemicals causing no thyroid changes. However, this correlation was far from perfect, with many chemicals producing thyroid proliferative lesions, but not liver neoplasms and vice versa. This suggests that universal correlations are not supportable by the data and that individual chemicals should be evaluated on a case-by-case basis.
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PMID:Thyroid follicular cell carcinogenesis: results from 343 2-year carcinogenicity studies conducted by the NCI/NTP. 143 97

The purpose of this study was to determine the carcinogenic effect in male rats of a single i.v. injection of N-methyl-N-nitrosourea (MNU) after sequential treatment with cyproterone acetate (for 21 days) and testosterone propionate (for 3 days). This treatment has previously been shown to induce carcinomas of the prostate and other male accessory sex glands. A wide spectrum of non-melanoma skin tumors was found in 38-48% of Wistar (Cpb:WU) rats given this sequential treatment, but only in 5% of rats that received only MNU. Castration long and, particularly, early after MNU markedly reduced this skin tumor response to a 10-13% incidence. The skin tumorigenic efficacy of MNU was dependent on the time between the start of the testosterone propionate treatment and carcinogen administration: MNU injection after 48-50 or 60-63 h induced skin tumors in 17-21% of Wistar rats, whereas injection after 72-74 h induced a 48% incidence. The Fischer F344 and Sprague-Dawley strains were not very sensitive to induction of skin tumors by this approach. Thyroid follicular cell tumors were also induced by MNU only after the hormonal pretreatment, and their induction was influenced by the time of MNU injection as well. The time of MNU injection and rat strain used did not significantly influence the induction of sebaceous-squamous neoplasms of the ear-duct/Zymbal's glands or other tumors. These data indicate that endogenous androgens are critically involved in the later stages of rat skin tumorigenesis and suggest that androgen-induced cell proliferation influences the initiation stage of this process and, possibly, of thyroid tumorigenesis.
Carcinogenesis 1992 Apr
PMID:Induction of skin and thyroid tumors in male rats by N-methyl-N-nitrosourea after sequential treatment with cyproterone acetate and testosterone propionate: effects of castration, rat strain and time of carcinogen injection. 153 74

Thyroid tumours are a common finding in toxicity tests in rodents. It is known that prolonged administration of antithyroid drugs leads to the development of multiple thyroid tumours, and the role of genotoxic and non-genotoxic mechanisms in this needs definition. The role of drugs with an antithyroid action in thyroid carcinogenesis requires a knowledge of thyroid physiology. This review briefly discusses the anatomy and physiology of the thyroid before concentrating on the cellular pathology of the changes that take place in the transition from a normal to a neoplastic thyroid cell. The malignant cell is characterised by excess growth and invasiveness. The normal thyroid cell does not possess an unlimited growth potential because of a growth-desensitising mechanism (GDM) of the antioncogene type. Spontaneous thyroid carcinogenesis requires three key steps which are presumed to arise by mutation and clonal selection: the loss of the GDM, the acquisition of TSH-independent growth, and the acquisition of invasiveness. The sequence of the cell biological changes involved is not fully understood, but it has been shown that IGF-1 is a necessary co-factor for the growth-stimulating effect of TSH in the normal cell, and that autocrine production of IGF-1 is a feature of spontaneous thyroid adenomas. Another early change that has been shown in both experimental and human thyroid tumours is mutation of one of the ras oncogenes. In carcinogenesis due to the prolonged administration of an agent known to interfere with thyroid hormone metabolism and to induce a high TSH, two rather than three key steps will be required for carcinogenesis, as the development of TSH independent growth will not confer any selective advantage. We have shown that monoclonal lesions induced in this way regress when the goitrogen is withdrawn and therefore retain TSH dependence. The development of the other two key changes--the loss of the GDM and the acquisition of invasiveness--may be due to genotoxic or non-genotoxic mechanisms. They can occur in man in the absence of any known mutagenic agent. In patients with dyshormonogenesis a congenital defect in one of the steps of thyroid hormone synthesis is associated with multiple tumour production. It is reassuring that in these patients, exposed to decades of high TSH levels, benign lesions are common, but malignant thyroid tumours are very rare. The occurrence of thyroid tumours following the use of substances known to interfere with thyroid hormone metabolism does not itself exclude a genotoxic component to the carcinogenesis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Evidence for and possible mechanisms of non-genotoxic carcinogenesis in the rodent thyroid. 204 91

Thyroid hormone participates in numerous cellular functions besides thermogenesis and metabolism. Several studies, including the recent identification of the product of an oncogene, c-erb-A, as a thyroid-hormone receptor, have shown possible involvement of thyroid hormone in the process of carcinogenesis. A recent anecdotal observation of an unusually high incidence of thyroid dysfunction in women with renal cell carcinoma led to a retrospective review of the incidence and distribution of thyroid disorders in women with renal cell carcinoma compared with a control group of women with transitional cell carcinoma of the renal pelvis, ureter, bladder, or urethra. Women with renal cell carcinoma had a statistically significantly higher percentage of hypothyroidism, thyroid disease in general, and the use of thyroid-hormone supplements as compared with the control group (P = 0.033, P = 0.005, P = 0.041, respectively). The nature of the relationship, however, could not be determined. These findings add a new dimension to renal cell carcinoma, and prospective studies are encouraged to define the contribution of thyroid hormone to renal cell carcinogenesis.
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PMID:Relationship of thyroid disease to renal cell carcinoma. An epidemiologic study. 235 76

Thyroid dysfunction (induced by thyroidectomy or administration of thyroxin and methylthiouracil) during the postnatal period was tested as a modifying factor on carcinogenesis induced transplacentally by N-methyl-N-nitrosourea (MNU). It resulted mainly in inhibition of tumours of the nervous system and kidney in rats of two subsequent generations, but thyroid carcinogenesis was increased. Postnatal disturbance of oestrous function (induction of persistent oestrus syndrome) in female rats increased the incidence of tumours of the central nervous system induced transplacentally by MNU or 7,12-dimethylbenz[a]anthracene. No such effect was seen in animals of the F2 generation.
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PMID:Influence of hormonal disturbances on transplacental and multigeneration carcinogenesis in rats. 250 48

As model compounds of alpha-hydroxy N-nitrosamines, four alpha-hydroperoxy N-nitrosamines were tested for their carcinogenic potential in F344 rats by i.v. injections. Correlation between chemical structure and carcinogenic potencies with respect to target organs was examined. Compounds used in this study were N-methyl-N-(hydroperoxymethyl)nitrosamine (MHPMN), N-ethyl-N-(1-hydroperoxyethyl)nitrosamine (EHPEN), N-propyl-N-(1-hydroperoxypropyl)nitrosamine (PHPPN) and N-butyl-N-(1-hydroperoxybutyl)nitrosamine (BHPBN). All chemicals were dissolved in distilled water and rats received 10 X 1 weekly i.v. injections of these chemicals (10 X 1 weekly injection of 5 mg/kg of MHPMN or equimolar amounts of other chemicals). Lung tumors were detected in all groups of both sexes and the incidences were 100% in each group. Thyroid tumors were also observed with relatively high incidences in treated groups except BHPBN. In the control group, tumors were observed mainly in the testis or uterus, and only two lung tumors and one thyroid tumor were observed in females. Histologically, all lung tumors in the MHPMN group were adenocarcinomas, squamous cell carcinomas or a mixture of both types. In the EHPEN, PHPPN and BHPBN groups, especially in females, incidences of carcinomas decreased as the length of the alkyl chain of the compounds, and most of lung tumors in females of the PHPPN and BHPBN groups were adenomas. Many of the thyroid tumors observed in the treated groups were follicular adenomas/carcinomas, whereas C-cell adenomas were the most common type of spontaneous thyroid tumors in this strain of rats. These target organs were similar to those of alpha-acetoxy N-nitrosamines reported previously. The results indicate that the carcinogenic activities of these chemicals depend on the length of the alkyl chain and that organ specificity of these chemicals may differ from those of their mother compounds.
Carcinogenesis 1986 Aug
PMID:Carcinogenicity of N-alkyl-N-(1-hydroperoxyalkyl) nitrosamines after intravenous injections in F344 rats. 373 85

Six-week-old male F344 rats were divided into 4 groups. Rats in Groups 1 (n = 16) and 3 (n = 14) received a s.c. injection of N-bis(2-hydroxypropyl)nitrosamine (DHPN) (2800 mg/kg) in experimental week 1 while rats in Groups 2 (n = 5) and 4 (n = 5) received saline. From weeks 2-20, all rats were given an iodine deficient (I-def) diet and tap water. Groups 1 and 2 were killed for the measurements of thyroid-stimulating hormone (TSH), thyroxine (T4), the maximum thyroid width (MTW), thyroid weight, morphology, morphometrics and proliferating cell nuclear antigen (PCNA) labeling index (LI). The thyroids of the rats in Group 3 and 4 were surgically exposed and the MTWs were measured. These latter rats were given basal diet for 6 weeks to recover from iodine deficiency, and then killed for the same measurements. Thyroid nodular lesions in Group 1 rats were classified into five categories (NL0, NL1, NL2, NL3 and NL4) based upon incremental cellular and structural atypia. Two types of regressive nodules (NL'0 and NL'1+2) were identified in the recovered rats as the regressed form of NL0, NL1 and NL2 lesions. NL3 and NL4 nodules were seen in Groups 1 and 3. The mean number of combined NL0, NL1 or NL2 lesions was 28.44 +/- 6.12 nodules per rat (NPR) in Group 1 rats and the mean number of NL'0 and NL'1+2 lesions was 28.07 +/- 13.05 NPR in Group 3 rats. The mean number of NL3 or NL4 lesions was 1.70 NPR in Group 1 rats and 3.42 NPR in Group 3 rats. The LIs were NL0 (6.4 +/- 2.5%), NL1 (7.7 +/- 4.4%), NL2 (0.7 +/- 0.3%), NL3 (7.5 +/- 1.3%) and NL4 (14.4 +/- 5.3%) in Group 1 rats and NL'0 (< 0.001%), NL'1 + 2 (< 0.01%), NL3 (9.0 +/- 4.4%) and NL4 (23.3 +/- 17.8%) in Group 3 rats. The thyroid weights of Group 4 rats were 41% of Group 2 rats. The volume fraction (VF) of the non-NL3, non-NL4 areas in Group 3 rats was 40% of that in Group 1 rats. However, the VF of NL3 or NL4 lesions in Group 3 rats was 520% of that of Group 1 rats. In summary, the growth of the NL0, NL1 and NL2 lesions was TSH-dependent, whereas NL3 and NL4 lesions were TSH-independent.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1993 Nov
PMID:Regressive and non-regressive thyroid lesions of the rat induced by single injection of N-bis(2-hydroxypropyl)nitrosamine and iodine deficient diet. 790 19

Time course changes in serum TSH and quantitative data for thyroid proliferative lesions in male F344 rats administered N-bis(2-hydroxypropyl)nitrosamine (DHPN: 2000 mg/kg body weight, single s.c. injection) followed by 0.1% thiourea (TU), were assessed at weeks 1, 2, 4, 8, 12 and 16 of treatment. The serum T4 level in the TU group was markedly decreased at week 1 and remained significantly lowered throughout the experiment. Serum TSH levels, in contrast, were elevated up to a peak at around week 4 with a return to the normal range at week 12. Thyroid weights in the TU group were increased significantly in a treatment period-dependent manner. Histopathologically, marked hypertrophy of thyroid follicular cells occurred at the early stage of TU treatment. Proliferative lesions, such as hyperplasia and adenomas, occurred from weeks 2 and 4, respectively, and increased with the later treatment period. The cell proliferative activity of follicular cells, assessed by BrdU incorporation, was high until week 2, but then returned to normal. The initially appearing hyperplasias and adenomas were characterized by marked proliferation but this also greatly decreased at later stages when TSH was no longer elevated. The results of our study thus suggest that a high serum TSH level plays an important role in the early phase of thyroid tumorigenesis and 8 weeks treatment with test substances is sufficient for detection of thyroid tumor promoter potential in two-stage thyroid carcinogenesis models.
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PMID:Time course observation of thyroid proliferative lesions and serum TSH levels in rats treated with thiourea after DHPN initiation. 795 29

Thyroid tumorigenesis is discussed in the context of the thyroid as a stable tissue, composed of differentiated cells, with a greater dissociation of control of growth from control of differentiation than is found in stem cell tissues. Experimental thyroid carcinogenesis regimes usually use mutagen exposure followed by induced growth. The normal thyroid follicle cell has a limited growth capacity, so loss of one tumour suppressor gene followed by growth-associated loss of heterozygosity would allow escape from this growth limitation, and the formation of a neoplastic clone. In man, there are two pathways of tumour formation, one through follicular adenoma to follicular carcinoma, and one to papillary carcinoma. These two pathways show differing aetiology, and differing oncogene involvement. In the follicular carcinoma pathway TSH-induced growth is relevant as it is in experimental animals. Mutagenesis is important for both papillary and follicular carcinomas. Radiation mutagenesis is of particular current importance because of the occurrence of thyroid carcinoma in children exposed to fallout from Chernobyl. The greater capacity for post-mutagen growth in children than adults is likely to explain the increased radiosensitivity of children, both to external and internal radiation.
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PMID:Thyroid tumorigenesis. 795 31


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