AUTHOR=Duquette Mark , Sadow Peter M. , Lawler Jack , Nucera Carmelo 

TITLE=Thrombospondin-1 Silencing Down-Regulates Integrin Expression Levels in Human Anaplastic Thyroid Cancer Cells with BRAFV600E: New Insights in the Host Tissue Adaptation and Homeostasis of Tumor Microenvironment

JOURNAL=Frontiers in Endocrinology

VOLUME=4

YEAR=2013

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2013.00189

DOI=10.3389/fendo.2013.00189

ISSN=1664-2392

ABSTRACT=<p><bold>Background and Rationale</bold>: Anaplastic thyroid cancer (ATC) is characterized by pleomorphic cells, has a poor prognosis, is highly devastating disease, and is not curable. No reliable biomarkers of metastatic potential, helpful for early diagnosis of ATC and therapeutic response have been found yet. Thrombospondin-1 (TSP-1) plays a fundamental role in cancer progression by regulating cell stromal cross-talk in the tumor microenvironment.</p><p><bold>Goals</bold>: Our goal was to understand whether TSP-1 could affect protein levels of its integrin receptors (e.g., ITGα3, α6, and β1) and cell morphology in BRAF<sup>V600E</sup>-ATC cells <italic>in vitro</italic> and <italic>in vivo</italic>.</p><p><bold>Experimental Design</bold>: Anaplastic thyroid cancer-derived cell cultures and western blotting were used to assess integrin protein expression upon TSP-1 silencing. Immunohistochemistry was performed on orthotopic primary human ATC and metastatic ATC in lung tissue to compare TSP-1 and integrin protein expression levels.</p><p><bold>Results</bold>: TSP-1 knock-down down-regulates ITGα3, α6, and β1 in BRAF<sup>V600E</sup>-human ATC cells. BRAF<sup>V600E</sup>-ATC cells with TSP-1 knock-down were rounded compared to control cells, which displayed a spread morphology. TSP-1 knock-down also reduced TSP-1, ITGα3, α6, and β1 protein expression levels <italic>in vivo</italic> in the ATC microenvironment, which is enriched in stromal and inflammatory cells.</p><p><bold>Conclusion</bold>: TSP-1 silencing causes changes in ITG levels and ATC cell morphology. The assessment of TSP-1 and ITG levels might contribute to earlier metastatic potential of BRAF<sup>V600E</sup>-positive aggressive thyroid cancers, and allow improved patient selection for clinical trials.</p>