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000294419 0247_ $$2doi$$a10.1089/thy.2018.0526
000294419 0247_ $$2pmid$$apmid:31526103
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000294419 0247_ $$2ISSN$$a1557-9077
000294419 037__ $$aDKFZ-2024-02248
000294419 041__ $$aEnglish
000294419 082__ $$a610
000294419 1001_ $$aKohler, Hannah$$b0
000294419 245__ $$aIncreased Anaplastic Lymphoma Kinase Activity Induces a Poorly Differentiated Thyroid Carcinoma in Mice.
000294419 260__ $$aLarchmont, NY$$bLiebert$$c2019
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000294419 520__ $$aBackground: 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.
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000294419 650_7 $$2Other$$aALK
000294419 650_7 $$2Other$$aPDTC
000294419 650_7 $$2Other$$aanaplastic lymphoma kinase
000294419 650_7 $$2Other$$apoorly differentiated thyroid cancer
000294419 650_7 $$2NLM Chemicals$$aNkx2-1 protein, mouse
000294419 650_7 $$2NLM Chemicals$$aThyroid Nuclear Factor 1
000294419 650_7 $$09002-71-5$$2NLM Chemicals$$aThyrotropin
000294419 650_7 $$09010-34-8$$2NLM Chemicals$$aThyroglobulin
000294419 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aAlk protein, mouse
000294419 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aAnaplastic Lymphoma Kinase
000294419 650_2 $$2MeSH$$aAnaplastic Lymphoma Kinase: genetics
000294419 650_2 $$2MeSH$$aAnimals
000294419 650_2 $$2MeSH$$aCarcinoma: genetics
000294419 650_2 $$2MeSH$$aCarcinoma: pathology
000294419 650_2 $$2MeSH$$aCarcinoma: secondary
000294419 650_2 $$2MeSH$$aCell Dedifferentiation: genetics
000294419 650_2 $$2MeSH$$aHypothyroidism: etiology
000294419 650_2 $$2MeSH$$aHypothyroidism: metabolism
000294419 650_2 $$2MeSH$$aLung Neoplasms: secondary
000294419 650_2 $$2MeSH$$aMice
000294419 650_2 $$2MeSH$$aNeoplasm Invasiveness
000294419 650_2 $$2MeSH$$aThyroglobulin: metabolism
000294419 650_2 $$2MeSH$$aThyroid Neoplasms: genetics
000294419 650_2 $$2MeSH$$aThyroid Neoplasms: pathology
000294419 650_2 $$2MeSH$$aThyroid Nuclear Factor 1: metabolism
000294419 650_2 $$2MeSH$$aThyrotropin: metabolism
000294419 7001_ $$aLatteyer, Soeren$$b1
000294419 7001_ $$aHönes, Georg Sebastian$$b2
000294419 7001_ $$aTheurer, Sarah$$b3
000294419 7001_ $$aLiao, Xiao-Hui$$b4
000294419 7001_ $$aChristoph, Sandra$$b5
000294419 7001_ $$aZwanziger, Denise$$b6
000294419 7001_ $$aSchulte, Johannes H$$b7
000294419 7001_ $$aKero, Jukka$$b8
000294419 7001_ $$aUndeutsch, Hendrik$$b9
000294419 7001_ $$aRefetoff, Samuel$$b10
000294419 7001_ $$aSchmid, Kurt W$$b11
000294419 7001_ $$aFührer, Dagmar$$b12
000294419 7001_ $$aMoeller, Lars C$$b13
000294419 773__ $$0PERI:(DE-600)2030622-2$$a10.1089/thy.2018.0526$$gVol. 29, no. 10, p. 1438 - 1446$$n10$$p1438 - 1446$$tThyroid$$v29$$x1050-7256$$y2019
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