Growth activation alone is not sufficient to cause metastatic thyroid cancer in a mouse model of follicular thyroid carcinoma.
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) (TRbeta(PV/PV) mice). These mice, harboring a dominantly negative mutation (PV) of the thyroid hormone-beta receptor (TRbeta), exhibit increased serum thyroid hormone and elevated TSH. To eliminate TSH growth-stimulating effect, TRbeta(PV/PV) mice were crossed with TSH receptor gene knockout (TSHR(-/-)) mice. Wild-type siblings of TRbeta(PV/PV) mice were treated with an antithyroid agent, propylthiouracil, to elevate serum TSH for evaluating long-term TSH effect (WT-PTU mice). Thyroids from TRbeta(PV/PV)TSHR(-/-) showed impaired growth with no occurrence of FTC. Both WT-PTU and TRbeta(PV/PV) mice displayed enlarged thyroids, but only TRbeta(PV/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.
Laboratory of Molecular Biology, National Cancer Institute, 37 Convent Drive, Room 5128, Bethesda, Maryland 20892-4264, USA.
Changxue
C
Lu
Li
L
Zhao
Hao
H
Ying
Mark C
MC
Willingham
Sheue-Yann
SY
Cheng
D018263:Adenocarcinoma, Follicular / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D007150:Immunohistochemistry; D016023:Integrins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D013961:Thyroid Gland / Q000378:metabolism* / Q000473:pathology; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013972:Thyrotropin / Q000235:genetics / Q000378:metabolism; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
D016023:Integrins; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D013972:Thyrotropin; D013974:Thyroxine