The known facultative predisposing factors for the development of angiosarcoma in the cases studied were: chronic lymphedema in three cases and postirradiation status in two cases. whereas sarcomas with high Fas-L expression show significantly reduced numbers of TILs. These results suggest that the Fas/Fas-L system may repress TIL invasion into angiosarcoma and by this may contribute to the evasion of the anti-tumor immune surveillance of angiosarcoma in the course of an apoptotic tumor counterattack mechanism. Fas (CD95/APO-1) is usually a cell surface receptor of the nerve growth factor/tumor necrosis factor receptor superfamily. Its ligand, Fas-L, is usually structurally related to tumor necrosis factor, lymphotoxin, and CD40 ligand. Fas-L is usually membrane associated and can be released from your cells in a soluble form by proteolysis. Binding of Fas-L to Fas prospects to trimerization of the receptor and to the transmission of apoptotic signals via the so-called death domain, resident in the cytoplasmic domain name of Fas. Fas and Fas-L play a key role in the regulation of apoptosis within the immune system, especially in lymphocyte development, anti-viral immune responses, and the removal of tumor cells. Malfunction of the Fas/Fas-L pathway can cause lymphoproliferative disorders and acceleration of autoimmune diseases. 1,2 Fas and its ligand are highly expressed in activated T-cells, natural killer cells, Clorgyline hydrochloride CD34-positive stem cells, and several other nonimmune cells including endothelial cells (ECs). 1-9 Fas-L expression in ECs has been detected in main cultures of ECs and in tissues in the endothelium of arteries in the rabbit ear and in immunoprivileged sites, such as the human eye and testis. 10-13 It has been shown that endothelial Fas-L induces apoptosis Clorgyline hydrochloride in Fas-expressing immune cells adhering to the Clorgyline hydrochloride vessel wall. This mechanism may contribute to the control of leukocyte extravasation into tissues. 10-13 ECs in addition to Fas-L also express Fas, both in culture and in tissues in the blood vessels of the central nervous system, the placenta, and the skeletal muscle mass. 14 However, co-expression of Fas and Fas-L does not induce apoptosis in ECs. 10,11,15 These results suggest that EC-derived tumors may be resistant to cell-mediated anti-tumor defense mechanisms targeting the Fas/Fas-L system. The expression of Fas/Fas-L in EC-derived tumors has so far not been investigated. Here we investigated the expression of Fas and Fas-L in 40 angiosarcomas with different histopathological tumor grades. Fas protein was detected in 50% of the angiosarcomas. In the positive cases it was expressed in variable numbers of tumor Clorgyline hydrochloride cells and did not correlate with any parameter investigated in this study. By contrast, the level of Fas-L expression correlated significantly with a reduction of the numbers of CD3-positive and CD8-positive tumor-infiltrating lymphocytes (TILs). These findings suggest that the angiosarcoma cells may evade cellular anti-tumor responses of the host by a Fas-L-mediated apoptotic counterattack on TILs. Materials and Methods Patients The angiosarcoma collective (= 40) was composed of 18 females and 22 males (median age, 55 years; age range, 24 to 87 years). The localization of angiosarcomas included Rabbit Polyclonal to WAVE1 (phospho-Tyr125) the extremities (= 11, 27.5%), breast (= 6, 15%), head (= 4, 10%), heart, thyroid and liver (each = 3, each 7.5%), sternum and retroperitoneum (both = 2, both 5%) as well as the diaphragm, Clorgyline hydrochloride trunk, parotid gland, lung, pancreas, and pelvis (each = 1, each 2.5%). The known facultative predisposing factors for the development of angiosarcoma in the cases studied were: chronic lymphedema in three cases and postirradiation status in two cases. Thyroid angiosarcomas are known to show a predilection for inhabitants of mountainous regions (such as the Bavarian alpine region) with iodine deficiency and development of long-standing nodular goiter. 16 Anamnestical data on an occupational exposure to thorotrast (thorium dioxide), arsenic solutions, or vinyl chloride, which may be associated with the development of angiosarcomas were not found. Median survival was 339 days after diagnosis and survival ranged from 18 to 5446.