Growth activation alone is not sufficient to cause metastatic thyroid cancer in a mouse model of follicular thyroid carcinoma

Changxue Lu, Li Zhao, Hao Ying, Mark C. Willingham, Sheue Yann Cheng

Research output: Contribution to journalArticlepeer-review

Abstract

TSH is the major stimulator of thyrocyte proliferation, but its role in thyroid carcinogenesis remains unclear. To address this question, we used a mouse model of follicular thyroid carcinoma (FTC) (TRβPV/PV mice). These mice, harboring a dominantly negative mutation (PV) of the thyroid hormone-β receptor (TRβ), exhibit increased serum thyroid hormone and elevated TSH. To eliminate TSH growth-stimulating effect, TRβ PV/PV mice were crossed with TSH receptor gene knockout (TSHR -/-) mice. Wild-type siblings of TRβPV/PV mice were treated with an antithyroid agent, propylthiouracil, to elevate serum TSH for evaluating long-term TSH effect (WT-PTU mice). Thyroids from TRβPV/PVTSHR-/- showed impaired growth with no occurrence of FTC. Both WT-PTU and TRβPV/PV mice displayed enlarged thyroids, but only TRβPV/PV mice developed metastatic FTC. Molecular analyses indicate that PV acted, via multiple mechanisms, to activate the integrins-Src-focal adhesion kinase-p38 MAPK pathway and affect cytoskeletal restructuring to increase tumor cell migration and invasion. Thus, growth stimulated by TSH is a prerequisite but not sufficient for metastatic cancer to occur. Additional genetic alterations (such as PV), destined to alter focal adhesion and migration capacities, are required to empower hyperplastic follicular cells to invade and metastasize. These in vivo findings provide new insights in understanding carcinogenesis of the human thyroid.

Original languageEnglish (US)
Pages (from-to)1929-1939
Number of pages11
JournalEndocrinology
Volume151
Issue number4
DOIs
StatePublished - Apr 2010
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology

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