Tumor Cells and Cancer-Associated Fibroblasts: A Synergistic Crosstalk to Promote Thyroid Cancer

Laura Fozzatti,Sheue-yann Cheng 대한내분비학회 2020 Endocrinology and metabolism Vol.35 No.4

Thyroid cancer is the most common endocrine malignancy. Although most thyroid cancer patients are successfully treated and have an excellent prognosis, a percentage of these patients will develop aggressive disease and, eventually, progress to anaplastic thyroid cancer. Since most patients with this type of aggressive thyroid carcinoma will die from the disease, new treatment strategies are urgently needed. Tumor cells live in a complex and dynamic tumor microenvironment composed of different types of stromal cells. Cancer-associated fibroblasts (CAFs) are one of the most important cell components in the tumor microenvironment of most solid tumors, including thyroid cancer. CAFs originate mainly from mesenchymal cells and resident fibroblasts that are activated and reprogrammed in response to paracrine factors and cytokines produced and released by tumor cells. Upon reprogramming, which is distinguished by the expression of different marker proteins, CAFs synthesize and secret soluble factors. The secretome of CAFs directly impacts different functions of tumor cells. This bi-directional interplay between CAFs and tumor cells within the tumor microenvironment ends up fostering tumor cancer progression. CAFs are therefore key regulators of tumor progression and represent an under-explored therapeutic target in thyroid cancer.

Epigenetic Modifications: Novel Therapeutic Approach for Thyroid Cancer

Xuguang Zhu,Sheue-yann Cheng 대한내분비학회 2017 Endocrinology and metabolism Vol.32 No.3

The incidence of thyroid cancer is growing the fastest among all cancers in the United States, especially in women. The number of patients with thyroid neoplasm is part of an even larger number of patients who often need to undergo an operation to exclude a cancer diagnosis. While differentiated thyroid cancer (papillary thyroid cancer and follicular thyroid cancer) accounts for most cases of thyroid cancer and has a relatively good prognosis, effective treatments for patients with de-differentiated and anaplastic thyroid cancer are still gravely needed. Despite progress in the identification of genetic changes in thyroid cancer, the impact of aberrant epigenetic alterations on thyroid cancer remains to be fully elucidated. Understanding of the roles of epigenetic changes in thyroid cancer could open new opportunities for the identification of innovative molecular targets for novel treatment modalities, especially for anaplastic thyroid cancer for which treatment is very limited. This article briefly reviews the studies that exemplify the potential for and promise of using epigenetic regulators in the treatment of thyroid cancer.

Loss of Primary Cilia Results in the Development of Cancer in the Murine Thyroid Gland

이정의,이신애,장준영,김정태,설혜정,박기철,Xuguang Zhu,Sheue-yann Cheng,Jukka Kero,김준,송민호 한국분자세포생물학회 2019 Molecules and cells Vol.42 No.2

Communications at the interface between the apical membrane of follicular cells and the follicular lumen are critical for the homeostasis of thyroid gland. Primary cilia at the apical membrane of thyroid follicular cells may sense follicular luminal environment and regulate follicular homeostasis, although their role in vivo remains to be determined. Here, mice devoid of primary cilia were generated by thyroid follicular epithelial cell-specific deletion of the gene encoding intraflagellar transport protein 88 (Ift88 ). Thyroid follicular cell-specific Ift88-deficient mice showed normal folliculogenesis and hormonogenesis; however, those older than 7 weeks showed irregularly dilated and destroyed follicles in the thyroid gland. With increasing age, follicular cells with malignant properties showing the characteristic nuclear features of human thyroid carcinomas formed papillary and solid proliferative nodules from degenerated thyroid follicles. Furthermore, malignant tumor cells manifested as tumor emboli in thyroid vessels. These findings suggest that loss-of-function of Ift88/primary cilia results in malignant transformation from degenerated thyroid follicles.

Defective erythropoiesis caused by mutations of the thyroid hormone receptor α gene

Park, Sunmi,Han, Cho Rong,Park, Jeong Won,Zhao, Li,Zhu, Xuguang,Willingham, Mark,Bodine, David M.,Cheng, Sheue-yann,Grimes, H. Leighton Public Library of Science 2017 PLoS genetics Vol.13 No.9

<▼1><P>Patients with mutations of the <I>THRA</I> gene exhibit classical features of hypothyroidism, including erythroid disorders. We previously created a mutant mouse expressing a mutated TRα1 (denoted as PV; <I>Thra1</I><SUP>PV/+</SUP> mouse) that faithfully reproduces the classical hypothyroidism seen in patients. Using <I>Thra1</I><SUP>PV/+</SUP> mice, we explored how the TRα1PV mutant acted to cause abnormalities in erythropoiesis. <I>Thra1</I><SUP>PV/+</SUP> mice exhibited abnormal red blood cell indices similarly as reported for patients. The total bone marrow cells and erythrocytic progenitors were markedly reduced in the bone marrow of <I>Thra1</I><SUP>PV/+</SUP> mice. <I>In vitro</I> terminal differentiation assays showed a significant reduction of mature erythrocytes in <I>Thra1</I><SUP>PV/+</SUP> mice. In wild-type mice, the clonogenic potential of progenitors in the erythrocytic lineage was stimulated by thyroid hormone (T3), suggesting that T3 could directly accelerate the differentiation of progenitors to mature erythrocytes. Analysis of gene expression profiles showed that the key regulator of erythropoiesis, the <I>Gata-1</I> gene, and its regulated genes, such as the <I>Klf1</I>, <I>β-globin</I>, <I>dematin</I> genes, <I>CAII</I>, <I>band3 and eALAS</I> genes, involved in the maturation of erythrocytes, was decreased in the bone marrow cells of <I>Thra1</I><SUP>PV/+</SUP> mice. We further elucidated that the <I>Gata-1</I> gene was a T3-directly regulated gene and that TRα1PV could impair erythropoiesis via repression of the <I>Gata-1</I> gene and its regulated genes. These results provide new insights into how TRα1 mutants acted to cause erythroid abnormalities in patients with mutations of the <I>THRA</I> gene. Importantly, the <I>Thra1</I><SUP>PV/+</SUP> mouse could serve as a preclinical mouse model to identify novel molecular targets for treatment of erythroid disorders.</P></▼1><▼2><P><B>Author summary</B></P><P>Patients with mutations of the <I>THRA</I> gene exhibit erythroid disorders. The molecular pathogenesis underlying erythroid abnormalities is poorly understood. In <I>Thra1</I><SUP>PV/+</SUP> mice expressing a dominant negative mutant TRα1PV, we found abnormal red blood cell indices similar to patients. Total bone marrow cells, the clonogenic potential of erythrocytic progenitors, and terminal differentiation of erythrocytes were markedly decreased in <I>Thra1</I><SUP>PV/+</SUP> mice. We elucidated that <I>Gata-1</I>, a key erythroid gene, was directly positively regulated by TRα1. The erythroid defects in <I>Thra1</I><SUP>PV/+</SUP> mice were due, at least partly, to the TRα1PV-mediated suppression of the <I>Gata-1</I> gene and its down-stream target genes. Over-expression of <I>Gata-1</I> rescued impaired terminal differentiation. Our studies elucidated molecular mechanisms by which TRα1 mutants caused erythroid disorders in patients. The present study suggests that therapies aimed at GATA1 could be tested as a potential target in treating erythroid abnormalities in patients.</P></▼2>

Loss of Primary Cilia Results in the Development of Cancer in the Murine Thyroid Gland

Lee, Junguee,Yi, Shinae,Chang, Joon Young,Kim, Jung Tae,Sul, Hae Joung,Park, Ki Cheol,Zhu, Xuguang,Cheng, Sheue-yann,Kero, Jukka,Kim, Joon,Shong, Minho Korean Society for Molecular and Cellular Biology 2019 Molecules and cells Vol.42 No.2

Communications at the interface between the apical membrane of follicular cells and the follicular lumen are critical for the homeostasis of thyroid gland. Primary cilia at the apical membrane of thyroid follicular cells may sense follicular luminal environment and regulate follicular homeostasis, although their role in vivo remains to be determined. Here, mice devoid of primary cilia were generated by thyroid follicular epithelial cell-specific deletion of the gene encoding intraflagellar transport protein 88 (Ift88). Thyroid follicular cellspecific Ift88-deficient mice showed normal folliculogenesis and hormonogenesis; however, those older than 7 weeks showed irregularly dilated and destroyed follicles in the thyroid gland. With increasing age, follicular cells with malignant properties showing the characteristic nuclear features of human thyroid carcinomas formed papillary and solid proliferative nodules from degenerated thyroid follicles. Furthermore, malignant tumor cells manifested as tumor emboli in thyroid vessels. These findings suggest that loss-of-function of Ift88/primary cilia results in malignant transformation from degenerated thyroid follicles.

Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production

Hine, Christopher,Kim, Hyo-Jeong,Zhu, Yan,Harputlugil, Eylul,Longchamp, Alban,Matos, Marina Souza,Ramadoss, Preeti,Bauerle, Kevin,Brace, Lear,Asara, John M.,Ozaki, C. Keith,Cheng, Sheue-yann,Singha, S Cell Press 2017 Cell metabolism Vol.25 No.6

<▼1><P><B>Summary</B></P><P>Decreased growth hormone (GH) and thyroid hormone (TH) signaling are associated with longevity and metabolic fitness. The mechanisms underlying these benefits are poorly understood, but may overlap with those of dietary restriction (DR), which imparts similar benefits. Recently we discovered that hydrogen sulfide (H<SUB>2</SUB>S) is increased upon DR and plays an essential role in mediating DR benefits across evolutionary boundaries. Here we found increased hepatic H<SUB>2</SUB>S production in long-lived mouse strains of reduced GH and/or TH action, and in a cell-autonomous manner upon serum withdrawal in vitro. Negative regulation of hepatic H<SUB>2</SUB>S production by GH and TH was additive and occurred via distinct mechanisms, namely direct transcriptional repression of the H<SUB>2</SUB>S-producing enzyme cystathionine γ-lyase (CGL) by TH, and substrate-level control of H<SUB>2</SUB>S production by GH. Mice lacking CGL failed to downregulate systemic T<SUB>4</SUB> metabolism and circulating IGF-1, revealing an essential role for H<SUB>2</SUB>S in the regulation of key longevity-associated hormones.</P></▼1><▼2><P><B>Highlights</B></P><P>•<P>Hepatic H<SUB>2</SUB>S production capacity is elevated in long-lived hypopituitary mouse models</P>•<P>Growth hormone (GH) represses hepatic H<SUB>2</SUB>S production post-transcriptionally</P>•<P>Thyroid hormone (TH) acts via TRβ to repress cystathionine γ-lyase and H<SUB>2</SUB>S levels</P>•<P>H<SUB>2</SUB>S negatively regulates circulating TH and IGF-1 levels</P></P></▼2><▼3><P>Reduced thyroid hormone (TH) and growth hormone (GH) activity are hallmarks of genetic models of longevity in mice. Here, Hine et al. find that TH and GH negatively regulate hepatic production of the longevity-associated gas hydrogen sulfide, which feeds back to negatively regulate circulating TH and IGF-1 levels.</P></▼3>