{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T06:21:10Z","timestamp":1777875670878,"version":"3.51.4"},"reference-count":33,"publisher":"SAGE Publications","issue":"10","license":[{"start":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T00:00:00Z","timestamp":1569888000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      , we studied mice with thyrocyte-specific expression of a constitutively active ALK mutant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      Mice carrying a Cre-activated allele of a constitutively active ALK mutant (F1174L) were crossed with mice expressing tamoxifen-inducible Cre recombinase (CreER\n                      <jats:sup>T2<\/jats:sup>\n                      ) under the control of the thyroglobulin (Tg) gene promoter to achieve thyrocyte-specific expression of the ALK mutant (ALK\n                      <jats:sup>F1174L<\/jats:sup>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      ALK\n                      <jats:sup>F1174L<\/jats:sup>\n                      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 ALK\n                      <jats:sup>F1174L<\/jats:sup>\n                      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 ALK\n                      <jats:sup>F1174L<\/jats:sup>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>\n                      Expression of a constitutively activated ALK mutant in thyroids of mice leads to development of metastasizing thyroid cancer resembling human PDTC. These results demonstrate\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      that increased ALK activity is a driver mechanism in thyroid carcinogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/thy.2018.0526","type":"journal-article","created":{"date-parts":[[2019,9,17]],"date-time":"2019-09-17T02:10:40Z","timestamp":1568686240000},"page":"1438-1446","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":9,"title":["Increased Anaplastic Lymphoma Kinase Activity Induces a Poorly Differentiated Thyroid Carcinoma in Mice"],"prefix":"10.1177","volume":"29","author":[{"given":"Hannah","family":"Kohler","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, University of Duisburg-Essen, Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soeren","family":"Latteyer","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, University of Duisburg-Essen, Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georg Sebastian","family":"H\u00f6nes","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, University of Duisburg-Essen, Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Theurer","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University of Duisburg-Essen, Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-Hui","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Chicago, Chicago, Illinois."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Christoph","sequence":"additional","affiliation":[{"name":"Clinic for Bone Marrow Transplants, University Hospital Essen, University of Duisburg-Essen, Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denise","family":"Zwanziger","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, University of Duisburg-Essen, Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes H.","family":"Schulte","sequence":"additional","affiliation":[{"name":"Pediatric Oncology and Hematology, Charit\u00e9 University Medicine, Berlin, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jukka","family":"Kero","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland."},{"name":"Research Centre for Integrative Physiology and Pharmacology, Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hendrik","family":"Undeutsch","sequence":"additional","affiliation":[{"name":"Research Centre for Integrative Physiology and Pharmacology, Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel","family":"Refetoff","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Chicago, Chicago, Illinois."},{"name":"Department of Pediatrics, The University of Chicago, Chicago, Illinois."},{"name":"Committee on Genetics, The University of Chicago, Chicago, Illinois."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kurt W.","family":"Schmid","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University of Duisburg-Essen, Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dagmar","family":"F\u00fchrer","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, University of Duisburg-Essen, Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lars C.","family":"Moeller","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, University of Duisburg-Essen, Essen, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2019,10,15]]},"reference":[{"key":"e_1_3_4_2_2","article-title":"Grosse J 2017 Differentiated thyroid cancer-treatment: state of the art","volume":"18","author":"Schmidbauer B","unstructured":"Schmidbauer B, , Menhart K, , Hellwig D, Grosse J 2017 Differentiated thyroid cancer-treatment: state of the art. 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