TY  - JOUR
AU  - Kohler, Hannah
AU  - Latteyer, Soeren
AU  - Hönes, Georg Sebastian
AU  - Theurer, Sarah
AU  - Liao, Xiao-Hui
AU  - Christoph, Sandra
AU  - Zwanziger, Denise
AU  - Schulte, Johannes H
AU  - Kero, Jukka
AU  - Undeutsch, Hendrik
AU  - Refetoff, Samuel
AU  - Schmid, Kurt W
AU  - Führer, Dagmar
AU  - Moeller, Lars C
TI  - Increased Anaplastic Lymphoma Kinase Activity Induces a Poorly Differentiated Thyroid Carcinoma in Mice.
JO  - Thyroid
VL  - 29
IS  - 10
SN  - 1050-7256
CY  - Larchmont, NY
PB  - Liebert
M1  - DKFZ-2024-02248
SP  - 1438 - 1446
PY  - 2019
AB  - Background: Radioiodine refractory dedifferentiated thyroid cancer is a major clinical challenge. Anaplastic lymphoma kinase (ALK) mutations with increased ALK activity, especially fusion genes, have been suggested to promote thyroid carcinogenesis, leading to development of poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma. To determine the oncogenic potential of increased ALK activity in thyroid carcinogenesis in vivo, we studied mice with thyrocyte-specific expression of a constitutively active ALK mutant. Methods: Mice carrying a Cre-activated allele of a constitutively active ALK mutant (F1174L) were crossed with mice expressing tamoxifen-inducible Cre recombinase (CreERT2) under the control of the thyroglobulin (Tg) gene promoter to achieve thyrocyte-specific expression of the ALK mutant (ALKF1174L mice). Survival, thyroid hormone serum concentration, and tumor development were recorded. Thyroids and lungs were studied histologically. To maintain euthyroidism despite dedifferentiation of the thyroid, a cohort was substituted with levothyroxine (LT4) through drinking water. Results: ALKF1174L mice developed massively enlarged thyroids, which showed an early loss of normal follicular architecture 12 weeks after tamoxifen injection. A significant decrease in Tg and Nkx-2.1 expression as well as impaired thyroid hormone synthesis confirmed dedifferentiation. Histologically, the mice developed a carcinoma resembling human PDTC with a predominantly trabecular/solid growth pattern and an increased mitotic rate. The tumors showed extrathyroidal extension into the surrounding strap muscles and developed lung metastases. Median survival of ALKF1174L mice was significantly reduced to five months after tamoxifen injection. Reduced Tg expression and loss of follicular structure led to hypothyroidism with elevated thyrotropin (TSH). To test whether TSH stimulation played a role in thyroid carcinogenesis, we kept ALKF1174L mice euthyroid by LT4 substitution. These mice developed PDTC with identical histological features compared with hypothyroid mice, demonstrating that PDTC development was due to increased ALK activity and not dependent on TSH stimulation. Conclusion: Expression of a constitutively activated ALK mutant in thyroids of mice leads to development of metastasizing thyroid cancer resembling human PDTC. These results demonstrate in vivo that increased ALK activity is a driver mechanism in thyroid carcinogenesis.
KW  - Anaplastic Lymphoma Kinase: genetics
KW  - Animals
KW  - Carcinoma: genetics
KW  - Carcinoma: pathology
KW  - Carcinoma: secondary
KW  - Cell Dedifferentiation: genetics
KW  - Hypothyroidism: etiology
KW  - Hypothyroidism: metabolism
KW  - Lung Neoplasms: secondary
KW  - Mice
KW  - Neoplasm Invasiveness
KW  - Thyroglobulin: metabolism
KW  - Thyroid Neoplasms: genetics
KW  - Thyroid Neoplasms: pathology
KW  - Thyroid Nuclear Factor 1: metabolism
KW  - Thyrotropin: metabolism
KW  - ALK (Other)
KW  - PDTC (Other)
KW  - anaplastic lymphoma kinase (Other)
KW  - poorly differentiated thyroid cancer (Other)
KW  - Nkx2-1 protein, mouse (NLM Chemicals)
KW  - Thyroid Nuclear Factor 1 (NLM Chemicals)
KW  - Thyrotropin (NLM Chemicals)
KW  - Thyroglobulin (NLM Chemicals)
KW  - Alk protein, mouse (NLM Chemicals)
KW  - Anaplastic Lymphoma Kinase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:31526103
C2  - pmc:PMC8935483
DO  - DOI:10.1089/thy.2018.0526
UR  - https://inrepo02.dkfz.de/record/294419
ER  -