Levels and patterns of expression of hypoxia-inducible factor-1α, vascular endothelial growth factor, glucose transporter-1 and CD105 in adenoid cystic carcinomas with high-grade transformation.

AIMS: To compare the expression of proteins regulated by hypoxia between adenoid cystic carcinoma (ACC) with and without high-grade transformation (HGT). METHODS AND RESULTS: In eight ACC-HGT and 18 ACC without HGT, expression of hypoxia-inducible factor-1 (HIF-1α), vascular endothelial growth factor (VEGF), glucose transporter-1 (GLUT-1) and microvascular density (MVD) by CD105 (a hypoxia-inducible protein expressed in angiogenic endothelial cells) was determined. Expression levels of HIF-1α and VEGF as well as CD105-MVD did not differ significantly between: (i) transformed and conventional areas (TA and CA, respectively) of ACC-HGT, (ii) CA and ordinary ACC. HIF-1α was detected in 100% of cases and presented a diffuse expression pattern. No significant association was found between levels of HIF-1α expression and tumour size, metastasis and recurrence. GLUT-1 showed a prostromal expression pattern and was observed exclusively in TA (three of six cases) and in only three of 14 ACC. CONCLUSIONS: Both the absence of significant alterations in levels of expression of HIF-1α, VEGF and CD105 and the patterns of expression of HIF-1α and GLUT-1 suggest that hypoxia may not play a key role in the process of high-grade transformation of ACC. Although HIF-1α expression is a common finding in ACC, it cannot be used as a marker of tumour aggressiveness.

Angiogenic and lymphangiogenic microvessel density in recurrent pleomorphic adenoma.

BACKGROUND: Recurrent pleomorphic adenoma (RPA) is an uncommon and challenging disease. The aim of this study was to determine if there is a difference between RPA and the pleomorphic adenoma (PA) without recurrence related to tumor blood and lymphatic vascularization. Moreover, we compared the microvessel density (MVD) between cell-rich areas (predominance of epithelial cells) and cell-poor areas (predominance of myxoid and chondroid areas) of the stroma of PA and RPA. In addition, immunohistochemical staining for the Ki-67 antigen was conducted simultaneously to evaluate cell proliferation in PA and RPA. METHODS: A total of 19 cases of PA and 24 cases of RPA, blood, and lymphatic vessels were analyzed by immunohistochemical technique using the antibodies CD34, CD105, D2-40, and Ki-67. RESULTS: Comparing no recurrent with recurrent tumor, no significant difference was found in terms of lymphatic vessel density, MVD, and proliferation index. When MVD and proliferation index were compared with different areas in cellular composition (cell-rich and cell-poor areas), there was a significant difference in PA, as well as in RPA. CONCLUSION: This study shows that although RPA presents more aggressive clinical behavior than PA, there is no difference between tumor blood and lymphatic vascularization, suggesting that there is no correlation between vascularity and risk of recurrence. Furthermore, vascularized stroma in PA, as well as RPA, depends on the proportion of the cellular composition.

The 15d­PGJ2 hydrogel ameliorates atopic dermatitis through suppression of the immune response.

The present study examined the efficacy of the topical 15d­PGJ2­poloxamer 407 hydrogel in an atopic dermatitis (AD) animal model. The 15d­PGJ2 hydrogel was prepared and characterized. The examined rats possessed AD­Like cutaneous lesions, which were induced using 2,4­dinitrochlorobenzene, the rats were then treated with a hydrogel vehicle, 15d­PGJ2 hydrogel or tacrolimus for 14 days. The rats were sacrificed and blood samples were collected to quantify the IgE levels. Subsequently, skin biopsies were stained with toluidine blue to identify mast cells and immunohistochemistry was performed for ROR­Î³t and TNF­α. Histological analyses demonstrated that 15d­PGJ2 hydrogel significantly decreased mast cell infiltration (P<0.05) when compared with the AD­group. Tacrolimus at 0.1% exhibited decreased mast cell infiltration; however, this difference was not statistically significant from the AD­group. Topical 15d­PGJ2 hydrogel and Tacrolimus 0.1% significantly reduced the serum levels of IgE (P<0.05) compared with the AD­group. Immunohistochemistry revealed a significant decrease in ROR­Î³t and TNF­α positive cell expression (P<0.05) in the 15d­PGJ2 hydrogel group compared with the AD­group. In summary, topical administration of 15d­PGJ2 hydrogel had a beneficial effect on AD symptoms, suggesting that this formulation may be a useful strategy for the treatment of AD.

Expression of the vascular endothelial growth factor and angiopoietins in mucoepidermoid carcinoma of salivary gland.

Disrupted coordination of angiogenesis regulating signals, among them the vascular endothelial growth factor (VEGF) and angiopoietins (Angs), has been associated with abnormal angiogenesis and tumor progression. While VEGF induces endothelial cell proliferation, thereby initiating vessel formation, Angs are subsequently required for mural cell attachment, thus influencing remodeling and maturation of this vasculature. In addition to tumor cell, endothelial and mural cells, as well as myofibroblasts may also contribute to the secretion of these factors. In this study, we have analyzed by immunohistochemistry the expression of VEGF, Ang-1, Ang-2 and the Angs receptor Tie2 in both the stroma and tumor cells of mucoepidermoid carcinoma (MEC) of salivary gland. We have demonstrated that when myofibroblasts were detected adjacent to the cancer cells, they were frequently associated with intense positive staining for Ang-1 and Ang-2, and no reactivity to VEGF and Tie2. These myofibroblast-rich Ang-1 and Ang-2-stained areas were more commonly found in high-grade MEC cases than in low-grade ones. As for the malignant cells, they frequently expressed all proteins studied, but Ang-2 and VEGF were detected at higher levels compared to Ang-1 and Tie2. Our results indicate that the MEC environment favors cooperative activity between Angs and VEGF in modulating vascular growth and tumor aggressiveness.

Peroxiredoxin I, platelet-derived growth factor A, and platelet-derived growth factor receptor alpha are overexpressed in carcinoma ex pleomorphic adenoma: association with malignant transformation.

Carcinoma ex pleomorphic adenoma is a rare salivary gland malignancy. It constitutes an important model for the study of carcinogenesis, as it can display the tumor in different stages of progression, from benign pleomorphic adenoma to frankly invasive carcinoma. Growth signaling pathways undergo continuous activation in human tumors, commonly as a consequence of the overexpression of ligands and receptors such as platelet-derived growth factor and platelet-derived growth factor receptor. Hydrogen peroxide is produced after platelet-derived growth factor receptor activation, and it is essential for the sequential phosphorylation cascade that drives cell proliferation and migration. By their ability to degrade hydrogen peroxide, peroxiredoxins are involved in growth factor signaling regulation and in the oxidative stress response. To verify the potential association of peroxiredoxin I, platelet-derived growth factor-A, and platelet-derived growth factor receptor-alpha with carcinoma ex pleomorphic adenoma progression, we investigated the expression of these molecules in carcinoma ex pleomorphic adenoma showing different degrees of invasion. The peroxiredoxin I, platelet-derived growth factor-A, and platelet-derived growth factor receptor-alpha proteins were present in remnant pleomorphic adenoma to only a small extent, but, collectively, they were highly expressed as soon as the malignant phenotype was achieved and remained at elevated concentrations during progression to the advanced stages of carcinoma ex pleomorphic adenoma. In addition, their locations overlapped significantly, strengthening their connection to this growth-signaling pathway. Our results indicate that carcinoma ex pleomorphic adenoma cells acquire at least 2 significant advantages relative to their normal counterparts: resistance to oxidative stress-induced apoptosis, conferred by high peroxiredoxin I concentrations, and sustained growth, reflecting platelet-derived growth factor-A and platelet-derived growth factor receptor-alpha overexpression.