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@ARTICLE{Kohler:294419,
      author       = {H. Kohler and S. Latteyer and G. S. Hönes and S. Theurer
                      and X.-H. Liao and S. Christoph and D. Zwanziger and J. H.
                      Schulte and J. Kero and H. Undeutsch and S. Refetoff and K.
                      W. Schmid and D. Führer and L. C. Moeller},
      title        = {{I}ncreased {A}naplastic {L}ymphoma {K}inase {A}ctivity
                      {I}nduces a {P}oorly {D}ifferentiated {T}hyroid {C}arcinoma
                      in {M}ice.},
      journal      = {Thyroid},
      volume       = {29},
      number       = {10},
      issn         = {1050-7256},
      address      = {Larchmont, NY},
      publisher    = {Liebert},
      reportid     = {DKFZ-2024-02248},
      pages        = {1438 - 1446},
      year         = {2019},
      abstract     = {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.},
      keywords     = {Anaplastic Lymphoma Kinase: genetics / Animals / Carcinoma:
                      genetics / Carcinoma: pathology / Carcinoma: secondary /
                      Cell Dedifferentiation: genetics / Hypothyroidism: etiology
                      / Hypothyroidism: metabolism / Lung Neoplasms: secondary /
                      Mice / Neoplasm Invasiveness / Thyroglobulin: metabolism /
                      Thyroid Neoplasms: genetics / Thyroid Neoplasms: pathology /
                      Thyroid Nuclear Factor 1: metabolism / Thyrotropin:
                      metabolism / ALK (Other) / PDTC (Other) / anaplastic
                      lymphoma kinase (Other) / poorly differentiated thyroid
                      cancer (Other) / Nkx2-1 protein, mouse (NLM Chemicals) /
                      Thyroid Nuclear Factor 1 (NLM Chemicals) / Thyrotropin (NLM
                      Chemicals) / Thyroglobulin (NLM Chemicals) / Alk protein,
                      mouse (NLM Chemicals) / Anaplastic Lymphoma Kinase (NLM
                      Chemicals)},
      ddc          = {610},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31526103},
      pmc          = {pmc:PMC8935483},
      doi          = {10.1089/thy.2018.0526},
      url          = {https://inrepo02.dkfz.de/record/294419},
}