Abstract 3138: Stat3 signaling in thyroid cancer

Abstract

Abstract In this study, we addressed the relevance and regulation of Stat3 activation in thyroid cancer. Papillary Thyroid Carcinoma (PTC) comprises almost 80% of thyroid neoplasias and 70% of PTC present activating alterations of components of the ERK-MAPK pathway, either BRAF mutations, RET/PTC rearrangements or RAS mutations. PTCs often display a strong desmoplastic reaction, where tumor is surrounded by a dense stroma and infiltrated with inflammatory cells. To examine the role of Stat3 in thyroid tumours and its putative relation to the associated inflammatory reaction, we analysed Stat3 activation (i.e. Y705-phosphorylation) by IHC in 58 samples of PTC. Approximately 50% of the tumors express pStat3. Frequently, nuclear positivity is only observed in the edge of the tumor as well as in the thyroid cells within tumor stroma. The inner part of the tumor is generally negative. Using multiple cell line models of PTC we observe that both RET/PTC and BRAFV600E expression can lead to Stat3 activation. Similarly, transgenic models of both BRAFV600E and RET/PTC also demonstrate high levels of pStat3 in particular on the inflammatory/leading edge of the tumor. We hypothesize that Stat3 activation, particularly in BRAFV600E tumors, may result from a paracrine effect of stromal cells-derived factors in the adjacent tumor cells. Stat3 is principally activated by autocrine/paracrine IL-6/Jak signaling in lung and breast tumors. Similarly, here we demonstrate that pan-Jak inhibitors block Stat3 activation in PTC cell lines. Furthermore, IL-6 signaling appears to mediate Stat3 activation in RET/PTC, BRAFV600E and RAS expressing cell lines. BRAFV600E knockdown led to a significant decrease of IL-6 levels, as well as of pStat3. In conclusion, we have found that Stat3 is activated in PTC, and that, particularly in BRAFV600E tumors, such activation may result from a paracrine effect of stromal cells through upregulation of IL-6/Jak pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3138.