TY - JOUR
T1 - Growth activation alone is not sufficient to cause metastatic thyroid cancer in a mouse model of follicular thyroid carcinoma
AU - Lu, Changxue
AU - Zhao, Li
AU - Ying, Hao
AU - Willingham, Mark C.
AU - Cheng, Sheue Yann
PY - 2010/4
Y1 - 2010/4
N2 - 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.
AB - 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.
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U2 - 10.1210/en.2009-1017
DO - 10.1210/en.2009-1017
M3 - Article
C2 - 20133453
AN - SCOPUS:77950267114
SN - 0013-7227
VL - 151
SP - 1929
EP - 1939
JO - Endocrinology
JF - Endocrinology
IS - 4
ER -