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Matthew D Ringel

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John E Phay and Matthew D Ringel

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 and Matthew D Ringel

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, Xiaoli Zhang, Matthew D Ringel, and Sissy M Jhiang

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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Christina M Knippler, Motoyasu Saji, Neel Rajan, Kyle Porter, Krista M D La Perle, and Matthew D Ringel

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, Motoyasu Saji, Xiaoli Zhang, David Jarjoura, Alfredo Fusco, Vasyl V Vasko, and Matthew D Ringel

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.

Open access

Ying Ni, Spencer Seballos, Shireen Ganapathi, Danielle Gurin, Benjamin Fletcher, Joanne Ngeow, Rebecca Nagy, Richard T Kloos, Matthew D Ringel, Thomas LaFramboise, and Charis Eng

Along with breast and endometrial cancers, thyroid cancer is a major component cancer in Cowden syndrome (CS). Germline variants in SDHB/C/D (SDHx) genes account for subsets of CS/CS-like cases, conferring a higher risk of breast and thyroid cancers over those with only germline PTEN mutations. To investigate whether SDHx alterations at both germline and somatic levels occur in apparently sporadic breast cancer and differentiated thyroid cancer (DTC), we analyzed SDHx genes in the following four groups: i) 48 individuals with sporadic invasive breast adenocarcinoma for germline mutation; ii) 48 (expanded to 241) DTC for germline mutation; iii) 37 pairs DTC tumor-normal tissues for germline and somatic mutation and mRNA expression levels; and iv) data from 476 patients in the Cancer Genome Atlas thyroid carcinoma dataset for validation. No germline SDHx variant was found in a pilot series of 48 breast cancer cases. As germline SDHx variants were found in our pilot of 48 thyroid cancer cases, we expanded to three series of DTC comprising a total 754 cases, and found 48 (6%) with germline SDHx variants (P<0.001 compared with 0/350 controls). In 513 tumors, we found 27 (5%) with large somatic duplications within chromosome 1 encompassing SDHC. Both papillary and follicular thyroid tumors showed consistent loss of SDHC/D gene expression (P<0.001), which is associated with earlier disease onset and higher pathological-TNM stage. Therefore, we conclude that both germline and somatic SDHx mutations/variants occur in sporadic DTC but are very rare in sporadic breast cancer, and overall loss of SDHx gene expression is a signature of DTC.

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Samantha K McCarty, Motoyasu Saji, Xiaoli Zhang, Christina M Knippler, Lawrence S Kirschner, Soledad Fernandez, and Matthew D Ringel

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.

Free access

Manali Mody, Nachiket Dharker, Mark Bloomston, Pei-Shan Wang, Fu-Sheng Chou, Theodore S Glickman, Timothy McCaffrey, Zhaoqing Yang, Anne Pumfery, Daniel Lee, Matthew D Ringel, and Joseph J Pinzone

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.