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Matthew D Ringel Division of Endocrinology, Diabetes, and Metabolism and Cancer Biology Program, The Ohio State University Wexner Medical Center and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA

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Matthew D Ringel Division of Endocrinology, Diabetes, and Metabolism and Cancer Biology Program, The Ohio State University College of Medicine and Comprehensive Cancer Center, Columbus, Ohio, USA

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John E Phay Division of Surgical Oncology, Division of Endocrinology, Department of Surgery

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Matthew D Ringel Division of Surgical Oncology, Division of Endocrinology, Department of Surgery

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Thyroid cancer incidence is rising annually largely related to enhanced detection and early stage well-differentiated primary tumors. The prognosis for patients with early stage thyroid cancer is outstanding with most patients being cured with surgery. In selected cases, I-131 is administered to treat known or suspected residual or metastatic disease. Even patients with loco-regional metastases typically have an outstanding long-term prognosis, albeit with monitoring and occasional intervention for residual or recurrent disease. By contrast, individuals with distant metastases from thyroid cancer, particularly older patients with larger metastatic burdens and those with poorly differentiated tumors, have a poor prognosis. Patients with metastatic anaplastic thyroid cancer have a particularly poor prognosis. Published clinical trials indicate that transient disease control and partial remissions can be achieved with kinase inhibitor therapy directed toward angiogenic targets and that in some cases I-131 uptake can be enhanced. However, the direct targets of activity in metastatic lesions are incompletely defined and clear evidence that these treatments increase the duration or quality of life of patients is lacking, underscoring the need for improved knowledge regarding the metastatic process to inform the development of new therapies. In this review, we will focus on current data and hypotheses regarding key regulators of metastatic dormancy, metastatic progression, and the role of putative cancer stem cells.

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Fadi Nabhan Division of Endocrinology, Diabetes and Metabolism, The Ohio State University College of Medicine, Wexner Medical Center, Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA

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Matthew D Ringel Division of Endocrinology, Diabetes and Metabolism, The Ohio State University College of Medicine, Wexner Medical Center, Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA

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Thyroid cancer is an increasingly prevalent malignancy throughout the world. Management guidelines for both thyroid nodules and thyroid cancer have been published and updated by a number of societies internationally. All of these guidelines recognize this increasing incidence, particularly of small papillary thyroid cancers, due in part to improved technology enabling early or even ‘over’ diagnosis. Recent advances in molecular imaging and molecular methods have been developed to better characterize thyroid nodules, and a number of studies that have clarified risk stratification systems that can be modified over time allow for individualization of diagnosis, initial treatment, and subsequent follow-up strategies. Advances in surgical approaches and new treatments for patients with the most aggressive forms of thyroid cancer have all influenced management guidelines. Despite substantial similarities, there also are important differences between recent guidelines for some of the common clinical scenarios encountered by physicians in clinical practice. In the present manuscript, we will highlight similarities and differences between several of the most recently published guidelines focused on key areas of importance to clinical care and controversy. These are key areas for future research to strengthen the data to support future guideline recommendations.

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Yu-Yu Liu The Ohio State Biochemistry Program, Department of Physiology and Cell Biology, Molecular Virology, Internal Medicine
The Ohio State Biochemistry Program, Department of Physiology and Cell Biology, Molecular Virology, Internal Medicine

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Xiaoli Zhang The Ohio State Biochemistry Program, Department of Physiology and Cell Biology, Molecular Virology, Internal Medicine

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Matthew D Ringel The Ohio State Biochemistry Program, Department of Physiology and Cell Biology, Molecular Virology, Internal Medicine
The Ohio State Biochemistry Program, Department of Physiology and Cell Biology, Molecular Virology, Internal Medicine

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Sissy M Jhiang The Ohio State Biochemistry Program, Department of Physiology and Cell Biology, Molecular Virology, Internal Medicine
The Ohio State Biochemistry Program, Department of Physiology and Cell Biology, Molecular Virology, Internal Medicine
The Ohio State Biochemistry Program, Department of Physiology and Cell Biology, Molecular Virology, Internal Medicine

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The selective increase of Na+/I symporter (NIS)-mediated active iodide uptake in thyroid cells allows the use of radioiodine I131 for diagnosis and targeted treatment of thyroid cancers. However, NIS-mediated radioiodine accumulation is often reduced in thyroid cancers due to decreased NIS expression/function. As PI3K signaling is overactivated in many thyroid tumors, we investigated the effects of inhibitors for PI3K, Akt, or mTORC1 as well as their interplay on NIS modulation in thyroid cells under chronic TSH stimulation. PI3K inhibition by LY294002 increased NIS-mediated radioiodide uptake (RAIU) mainly through upregulation of NIS expression, however, mTORC1 inhibition by Rapamycin did not increase NIS-mediated RAIU despite increased NIS protein levels. In comparison, Akt inhibition by Akti-1/2 did not increase NIS protein levels, yet markedly increased NIS-mediated RAIU by decreasing iodide efflux rate and increasing iodide transport rate and iodide affinity of NIS. The effects of Akti-1/2 on NIS-mediated RAIU are not detected in nonthyroid cells, implying that Akti-1/2 or its derivatives may represent potential pharmacological reagents to selectively increase thyroidal radioiodine accumulation and therapeutic efficacy.

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Deborah J Marsh D Marsh, School of Life Sciences, Kolling Institute of Medical Research, Ultimo, 2007, Australia

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Lois M Mulligan L Mulligan, Pathology and Molecular Medicine, Queen's University, Kingston, Canada

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Joanne Ngeow J Ngeow, National Cancer Centre Singapore, National cancer Centre , singapore, Singapore

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Matthew D Ringel M Ringel, Medicine, The Ohio State University, Columbus, 43210, United States

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Constantine A Stratakis C Stratakis, NICHD, NIH, Bethesda, MD 20892, United States

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Matthew Ringel On behalf of the entire editorial team of Endocrine-Related Cancer, and personally as trainees and collaborators who at present serve as associate or senior editors of the Journal, it is with profound sadness that we write this memorial to Prof. Charis Eng, M.D., Ph.D who passed away on August 13, 2024. Prof. Eng served as Editor-in-Chief of Endocrine-Related Cancer from 2011-2021 and was dedicated to the Journal before, during, and after she served in that role. She had remarkable impact on Endocrine-Related Cancer moving the journal forward with great vision and energy while maintaining the strongest commitments to publishing the highest quality original research and reviews applying fair, ethical, and rigorous peer-review processes. Charis was a world-recognized leader in cancer genomics and clinical genetics medicine who enabled growth in Endocrine-Related Cancer in these and other areas critical for advancement of research and clinical care of endocrine cancers. She will be remembered by all of us as a superb and consequential researcher, editor, physician, leader, teacher, mentor, colleague, and friend.

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Christina M Knippler Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University Wexner Medical Center and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA

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Motoyasu Saji Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University Wexner Medical Center and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA

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Neel Rajan College of Arts and Sciences, The Ohio State University, Columbus, Ohio, USA

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Kyle Porter Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA

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Krista M D La Perle Department of Veterinary Biosciences, Comparative Pathology & Mouse Phenotyping Shared Resource, The Ohio State University, Columbus, Ohio, USA

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Matthew D Ringel Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University Wexner Medical Center and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA

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The number of individuals who succumb to thyroid cancer has been increasing and those who are refractory to standard care have limited therapeutic options, highlighting the importance of developing new treatments for patients with aggressive forms of the disease. Mutational activation of MAPK signaling, through BRAF and RAS mutations and/or gene rearrangements, and activation of PI3K signaling, through mutational activation of PIK3CA or loss of PTEN, are well described in aggressive thyroid cancer. We previously reported overactivation and overexpression of p21-activated kinases (PAKs) in aggressive human thyroid cancer invasive fronts and determined that PAK1 functionally regulated thyroid cancer cell migration. We reported mechanistic crosstalk between the MAPK and PAK pathways that are BRAF-dependent but MEK independent, suggesting that PAK and MEK inhibition might be synergistic. In the present study, we tested this hypothesis. Pharmacologic inhibition of group I PAKs using two PAK kinase inhibitors, G-5555 or FRAX1036, reduced thyroid cancer cell viability, cell cycle progression and migration and invasion, with greater potency for G-5555. Combination of G-5555 with vemurafenib was synergistic in BRAFV600E-mutated thyroid cancer cell lines. Finally, G-5555 restrained thyroid size of BRAFV600E-driven murine papillary thyroid cancer by >50% (P < 0.0001) and reduced carcinoma formation (P = 0.0167), despite maintenance of MAPK activity. Taken together, these findings suggest both that group I PAKs may be a new therapeutic target for thyroid cancer and that PAK activation is functionally important for BRAFV600E-mediated thyroid cancer development.

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Samantha K McCarty Division of Endocrinology, Department of Molecular Virology, Center for Biostatistics, Diabetes and Metabolism, Department of Internal Medicine

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Motoyasu Saji Division of Endocrinology, Department of Molecular Virology, Center for Biostatistics, Diabetes and Metabolism, Department of Internal Medicine

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Xiaoli Zhang Division of Endocrinology, Department of Molecular Virology, Center for Biostatistics, Diabetes and Metabolism, Department of Internal Medicine

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Christina M Knippler Division of Endocrinology, Department of Molecular Virology, Center for Biostatistics, Diabetes and Metabolism, Department of Internal Medicine

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Lawrence S Kirschner Division of Endocrinology, Department of Molecular Virology, Center for Biostatistics, Diabetes and Metabolism, Department of Internal Medicine
Division of Endocrinology, Department of Molecular Virology, Center for Biostatistics, Diabetes and Metabolism, Department of Internal Medicine

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Soledad Fernandez Division of Endocrinology, Department of Molecular Virology, Center for Biostatistics, Diabetes and Metabolism, Department of Internal Medicine

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Matthew D Ringel Division of Endocrinology, Department of Molecular Virology, Center for Biostatistics, Diabetes and Metabolism, Department of Internal Medicine
Division of Endocrinology, Department of Molecular Virology, Center for Biostatistics, Diabetes and Metabolism, Department of Internal Medicine

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Increased p21-activated kinase (PAK) signaling and expression have been identified in the invasive fronts of aggressive papillary thyroid cancers (PTCs), including those with RET/PTC, BRAFV600E, and mutant RAS expression. Functionally, thyroid cancer cell motility in vitro is dependent on group 1 PAKs, particularly PAK1. In this study, we hypothesize that BRAF, a central kinase in PTC tumorigenesis and invasion, regulates thyroid cancer cell motility in part through PAK activation. Using three well-characterized human thyroid cancer cell lines, we demonstrated in all cell lines that BRAF knockdown reduced PAK phosphorylation of direct downstream targets. In contrast, inhibition of MEK activity either pharmacologically or with siRNA did not reduce PAK activity, indicating MEK is dispensable for PAK activity. Inhibition of cell migration through BRAF loss is rescued by overexpression of either constitutive active MEK1 or PAK1, demonstrating that both signaling pathways are involved in BRAF-regulated cell motility. To further characterize BRAF–PAK signaling, immunofluorescence and immunoprecipitation demonstrated that both exogenously overexpressed and endogenous PAK1 and BRAF co-localize and physically interact, and that this interaction was enhanced in mitosis. Finally, we demonstrated that acute induction of BRAFV600E expression in vivo in murine thyroid glands results in increased PAK expression and activity confirming a positive signaling relationship in vivo. In conclusion, we have identified a signaling pathway in thyroid cancer cells which BRAF activates and physically interacts with PAK and regulates cell motility.

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Samantha K McCarty Divisions of Endocrinology and Oncology, Center for Biostatistics, Instituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Uniformed Services University of Health Science, The Ohio State University College of Medicine and Arthur G. James Comprehensive Cancer Center, 1581 Dodd Drive, 445D, Columbus, Ohio 43210, USA

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Motoyasu Saji Divisions of Endocrinology and Oncology, Center for Biostatistics, Instituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Uniformed Services University of Health Science, The Ohio State University College of Medicine and Arthur G. James Comprehensive Cancer Center, 1581 Dodd Drive, 445D, Columbus, Ohio 43210, USA

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Xiaoli Zhang Divisions of Endocrinology and Oncology, Center for Biostatistics, Instituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Uniformed Services University of Health Science, The Ohio State University College of Medicine and Arthur G. James Comprehensive Cancer Center, 1581 Dodd Drive, 445D, Columbus, Ohio 43210, USA

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David Jarjoura Divisions of Endocrinology and Oncology, Center for Biostatistics, Instituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Uniformed Services University of Health Science, The Ohio State University College of Medicine and Arthur G. James Comprehensive Cancer Center, 1581 Dodd Drive, 445D, Columbus, Ohio 43210, USA

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Alfredo Fusco Divisions of Endocrinology and Oncology, Center for Biostatistics, Instituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Uniformed Services University of Health Science, The Ohio State University College of Medicine and Arthur G. James Comprehensive Cancer Center, 1581 Dodd Drive, 445D, Columbus, Ohio 43210, USA

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Vasyl V Vasko Divisions of Endocrinology and Oncology, Center for Biostatistics, Instituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Uniformed Services University of Health Science, The Ohio State University College of Medicine and Arthur G. James Comprehensive Cancer Center, 1581 Dodd Drive, 445D, Columbus, Ohio 43210, USA

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Matthew D Ringel Divisions of Endocrinology and Oncology, Center for Biostatistics, Instituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Uniformed Services University of Health Science, The Ohio State University College of Medicine and Arthur G. James Comprehensive Cancer Center, 1581 Dodd Drive, 445D, Columbus, Ohio 43210, USA

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p21-activated kinases (PAKs) are a family of serine/threonine kinases that regulate cytoskeletal dynamics and cell motility. PAKs are subdivided into group I (PAKs 1–3) and group II (PAKs 4–6) on the basis of structural and functional characteristics. Based on prior gene expression data that predicted enhanced PAK signaling in the invasive fronts of aggressive papillary thyroid cancers (PTCs), we hypothesized that PAKs functionally regulate thyroid cancer cell motility and are activated in PTC invasive fronts. We examined PAK isoform expression in six human thyroid cancer cell lines (BCPAP, KTC1, TPC1, FTC133, C643, and SW1746) by quantitative reverse transcription-PCR and western blot. All cell lines expressed PAKs 1–4 and PAK6 mRNA and PAKs 1–4 protein; PAK6 protein was variably expressed. Samples from normal and malignant thyroid tissues also expressed PAKs 1–4 and PAK6 mRNA; transfection with the group I (PAKs 1–3) PAK-specific p21 inhibitory domain molecular inhibitor reduced transwell filter migration by ∼50% without altering viability in all cell lines (P<0.05). BCPAP and FTC133 cells were transfected with PAK1, PAK2, or PAK3-specific small interfering RNA (siRNA); only PAK1 siRNA reduced migration significantly for both cell lines. Immunohistochemical analysis of seven invasive PTCs demonstrated an increase in PAK1 and pPAK immunoactivity in the invasive fronts versus the tumor center. In conclusion, PAK isoforms are expressed in human thyroid tissues and cell lines. PAK1 regulates thyroid cancer cell motility, and PAK1 and pPAK levels are increased in PTC invasive fronts. These data implicate PAKs as regulators of thyroid cancer invasion.

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Manali Mody
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Nachiket Dharker
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Mark Bloomston
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Pei-Shan Wang
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Fu-Sheng Chou
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Theodore S Glickman
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Timothy McCaffrey
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Zhaoqing Yang
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Anne Pumfery
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Daniel Lee
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Matthew D Ringel
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Joseph J Pinzone
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Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear hormone superfamily and has multiple endogenous and pharmacological ligands, including 15-deoxy-Δ 12,14-prostaglandin J2 and two thiazolidinediones (TZD), rosiglitazone and pioglitazone, which are used clinically to treat type-2 diabetes mellitus. PPARγ agonists regulate development, cellular growth and metabolism in various tissues and have been documented to decrease cellular proliferation and to induce apoptosis of various tumour phenotypes, including breast cancer. However, the full spectrum of anti-tumour effects occurs only at suprapharmacological doses. In this study, we investigated the mechanism of rosiglitazone-induced anti-tumour effects of MDA-MB-231 human breast cancer cells, and used that information to predict rosiglitazone-induced sensitization of breast cancer cells to the effects of other compounds. We first confirmed that 100 μM rosiglitazone, but not lower doses, decreases MDA-MB-231 cell viability in vitro. We then used microarray gene expression analysis to determine early rosiglitazone-induced gene expression changes after 4-h exposure, which included 1298 genes that we grouped into functional categories. We selectively confirmed rosiglitazone-mediated effects on expression of key regulators of breast cancer proliferation and apoptosis, including p53, p21 and Bax. Finally, we used this information to predict that rosiglitazone would sensitize MDA-MB-231 cells to the anti-tumour effects of CH11, which trimerizes Fas, as well as tumour necrosis factor-α. Moreover, we used the confirmed array data to predict cooperative activity of rosiglitazone and R-roscovitine (CYC202), an inhibitor of multiple cyclin-dependent kinases. We conclude that microarray analysis can determine early TZD-modulated changes in gene expression that help to predict effective in vitro drug combinations.

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