title: Evidence for and possible mechanisms of non-genotoxic carcinogenesis in the rodent thyroid.
abstract: 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 We have shown that monoclonal lesions induced in this way regress when the goitrogen is withdrawn and therefore retain TSH dependence.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)
authors.affiliation: Department of Pathology, University of Wales College of Medicine, Heath Park, Cardiff, U.K.
authors.forename: G A
authors.initials: GA
authors.lastname: Thomas
authors.forename: E D
authors.initials: ED
authors.lastname: Williams
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D006801:Humans; D051379:Mice; D009153:Mutagens; D051381:Rats; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism
chemical_list: D002273:Carcinogens; D009153:Mutagens