Liotti, Federica (2010) Mast cells and their mediators in thyroid cancer. [Tesi di dottorato] (Unpublished)

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ABSTRACT Experimental, clinical, and epidemiological studies have demonstrated a strong association between inflammation and cancer. Evidence has emerged in the last two decades that at the molecular level most chronic diseases, including cancer, are caused by a dysregulated inflammatory response. Moreover, tumor stroma induces an inflammatory microenviroment that sustains tumor growth. Cytokines and chemokines secreted by stromal and cancer cells can have a two-sided effect as they can influence both leukocyte infiltration in tumor sites and the malignant phenotype of neoplastic cells. Thyroid cancer cells express several cytokines and chemokines that are modulated by the RET/PTC-ras-BRAF-ERK pathway. Among those, we focused on CXCL1 and VEGF. In this thesis, we show that thyroid cancer cell feature on CXCR2/CXCL1 autocrine loop that sustains proliferation, survival and invasiveness. Moreover, we focus on VEGF-A. Using chemoattraction assays, we show that thyroid cancer cells attract mast cells through the release of VEGF-A. Human mast cells, injected in the tail vein of athymic mice, were recruited to xenografts of human thyroid cancer cells. Human thyroid carcinomas feature a remarkable mast cell infiltrate whose intensity correlates with the invasive phenotype. Co-injection of human mast cells and 8505-C cells accelerated the growth of thyroid carcinoma xenograft in athymic mice and this effect could be blocked by sodium cromoglycate (Cromolyn), a specific mast cell inhibitor. We also show that thyroid cancer cells stimulate histamine release and cytokine synthesis in human mast cells. Moreover, mast cell-released mediators enhanced the proliferation, survival and invasive behavior of thyroid cancer cells in vitro.

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