The clinical behavior of
thyroid cancers is seen to reflect inherent transcriptional activities of mutated genes and trophic effects on
tumors of circulating pituitary
thyrotropin (TSH). The
thyroid hormone,
L-thyroxine (T4), has been shown to stimulate proliferation of a large number of different forms of
cancer. This activity of T4 is mediated by a
cell surface receptor on the extracellular domain of
integrin αvβ3. In this brief review, we describe what is known about T4 as a circulating trophic factor for differentiated (papillary and follicular)
thyroid cancers. Given T4's
cancer-stimulating activity in differentiated
thyroid cancers, it was not surprising to find that genomic actions of T4 were anti-apoptotic. Transduction of the T4-generated signal at the
integrin primarily involved
mitogen-activated protein kinase (MAPK). In thyroid C cell-origin
medullary carcinoma of the thyroid (MTC), effects of
thyroid hormone analogues, such as
tetraiodothyroacetic acid (
tetrac), include pro-angiogenic and apoptosis-linked genes.
Tetrac is an inhibitor of the actions of T4 at αvβ3, and it is assumed, but not yet proved, that the anti-angiogenic and pro-apoptotic actions of
tetrac in MTC cells are matched by T4 effects that are pro-angiogenic and anti-apoptotic. We also note that
papillary thyroid carcinoma cells may express the
leptin receptor, and circulating
leptin from adipocytes may stimulate
tumor cell proliferation. Transcription was stimulated by
leptin in anaplastic, papillary, and follicular
carcinomas of genes involved in invasion, such as
matrix metalloproteinases (
MMPs). In summary,
thyroid hormone analogues may act at their receptor on
integrin αvβ3 in a variety of types of
thyroid cancer to modulate transcription of genes relevant to
tumor invasiveness, apoptosis, and angiogenesis. These effects are independent of TSH.