Publications by Year: 2016

Cachexia is the result of complex metabolic alterations which cause morbidity and mortality in patients with advanced cancers including undifferentiated (anaplastic) thyroid carcinoma (ATC). ATC is a lethal disease with limited therapeutic options and unclear etiology for cachexia. We hypothesize that the BRAF(V600E) oncoprotein triggers microvascular endothelial cell tubule formation (in vitro angiogenesis) by means of factors which play a crucial role in angiogenic switch, inflammation/immune response and cachexia. We use human ATC cells and applied multiplex ELISA assay to screen for and measure angiogenic/cachectic and pro-inflammatory factors in the ATC-derived secretome. We find that vemurafenib anti-BRAF(V600E) therapy significantly reduces secreted VEGFA, VEGFC and IL6 protein levels compared to vehicle-treated ATC cells. As a result, the secretome from vemurafenib-treated ATC cells inhibits microvascular endothelial cell-related in vitro angiogenesis. Furthermore, ATC clinical samples express VEGFA, VEGFC and IL6 proteins. Our results suggest that angiogenic/cachectic and pro-inflammatory/immune response factors could play a crucial role in BRAF(V600E)-positive human ATC aggressiveness. Understanding the extent to which microenvironment-associated angiogenic factors participate in cachexia and cancer metabolism in advanced thyroid cancers will reveal new biomarkers and foster novel therapeutic approaches.

Iodide is a micronutrient essential for thyroid hormone production. The uptake and metabolism of iodide by thyrocytes is crucial to proper thyroid function. Iodide ions are drawn into the thyroid follicular cell via the sodium-iodide symporter (NIS) in the cell membrane and become integrated into tyrosyl residues to ultimately form thyroid hormones. We sought to learn how an abnormal concentration of iodide within thyrocyte can have significant effects on the thyroid, specifically the surrounding vascular network. Insufficient levels of iodide can lead to increased expression or activity of several pathways, including vascular endothelial growth factor (VEGF). The VEGF protein fuel vessel growth (angiogenesis) and therefore enhances the nutrients available to surrounding cells. Alternatively, normal/surplus iodide levels can have inhibitory effects on angiogenesis. Varying levels of iodide in the thyroid can influence thyroid carcinoma cell proliferation and angiogenesis via regulation of the hypoxia inducible factor-1 (HIF-1) and VEGF-dependent pathway. We have reviewed a number of studies to investigate how the effect of iodide on angiogenic and oxidative stress regulation can affect the viability of thyroid carcinoma cells. The various studies outlined give key insights to the role of iodide in thyroid follicles function and vascular growth, generally highlighting that insufficient levels of iodide stimulate pathways resulting in vascular growth, and viceversa normal/surplus iodide levels inhibit such pathways. Intriguingly, TSH and iodine levels differentially regulate the expression levels of angiogenic factors. All cells, including carcinoma cells, increase uptake of blood nutrients, meaning the vascular profile is influential to tumor growth and progression. Importantly, variation in the iodine concentrations also influence BRAFV600E-mediated oncogenic activity and might deregulate tumor proliferation. Although the mechanisms are not well eluted, iodine concentrations and metabolism might have a crucial influence on thyroid carcinoma cell viability via regulation of different molecular pathways, including angiogenesis regulatory autocrine and microenvironment-mediated signals.