Angiogenesis, lymphangiogenesis and atopic dermatitis.

Angiogenesis and morphological and functional alterations of microvessels are hallmark features of chronic inflammatory disorders, including certain skin diseases. Vascular endothelial growth factors (VEGFs) are key regulators of blood vessel growth. The VEGF family includes VEGF-A, -B, -C, -D and placental growth factor. VEGF-A and -B are the most important proangiogenic factors, while VEGF-C and -D primarily regulate lymphangiogenesis. Angiopoietins are promoters of neovascularization by interacting with Tie-1 and Tie-2 receptors present on endothelial cells. High levels of VEGF-A have been detected in skin tissue of atopic dermatitis (AD) patients and correlate with disease activity. The vascular changes in the skin of AD patients appear to be linked to the inflammatory process. Effector cells of skin inflammation (human mast cells, basophils, eosinophils, macrophages, lymphocytes, etc.) are major sources of a vast array of angiogenic and lymphangiogenic factors. The role of lymphangiogenesis in AD is largely unknown.

Mast cells have a protumorigenic role in human thyroid cancer.

In different human carcinoma types, mast cell infiltrate increases with respect to normal tissue and mast cell density correlates with a bad prognosis. To assess the role of mast cells in human thyroid cancer, we compared the density of tryptase-positive mast cells in 96 papillary thyroid carcinomas (PTCs) versus normal thyroid tissue from 14 healthy individuals. Mast cell density was higher in 95% of PTCs (n=91) than in control tissue. Mast cell infiltrate correlated with extrathyroidal extension (P=0.0005) of PTCs. We show that thyroid cancer cell-line-derived soluble factors induce mast cell activation and chemoattraction in vitro. Different mast cell lines (HMC-1 and LAD2) and primary human lung mast cells induced thyroid cancer cell invasive ability, survival and DNA synthesis in vitro. The latter effect was mainly mediated by three mast-cell-derived mediators: histamine, and chemokines CXCL1/GROα and CXCL10/IP10. We show that xenografts of thyroid carcinoma cells (8505-C) could recruit mast cells injected into the tail vein of mice. Co-injection of human mast cells accelerated the growth of thyroid cancer cell (8505-C) xenografts in athymic mice. This effect was mediated by increased tumor vascularization and proliferation, and was reverted by treating mice with sodium cromoglycate (Cromolyn), a specific mast cell inhibitor. In conclusion, our study data suggest that mast cells are recruited into thyroid carcinomas and promote proliferation, survival and invasive ability of cancer cells, thereby contributing to thyroid carcinoma growth and invasiveness.