ABSTRACT
Background: ADAMTS are metalloproteases with disintegrin and thrombospondin motifs. They are secreted proteases playing a role in biological processes such as inflammation, angiogenesis, and urogenital development. ADAMTS have specific substrates, such as the proteoglycans (PG) versican, aggrecan, and brevican. Despite data indicating a role of ADAMTS in tumor invasion and metastases, effects played by these molecules in cancer progression are still controversial. In ovarian cancer, the importance of ADAMTS gene mutations was recently described and related to chemotherapy outcome. Objective: To analyze protein levels of ADAMTS-1, -4, and -5, and TIMP-3 in human ovarian cancer classified as benign, borderline, or malignant. We also assessed the expression of the ADAMTS substrates aggrecan, brevican, and versican in these neoplasms. Correlations between overall survival and protein expression were performed. Methods: Tumors were classified according to the WHO Classification of Tumors of Female Reproductive Organs. Protein and PG expression was studied by immunohistochemistry. Differences in labeling were analyzed by percent measurements of stained areas. Results: ADAMTS-1, ADAMTS-5, and its tissue inhibitor TIMP-3 are increased in borderline and malignant tumors compared to benign neoplasms. Aggrecan and versican levels were increased in malignant subtypes compared to benign ovarian cancer. Higher ADAMTS-1, TIMP-3, and versican expression was associated with a shorter overall survival. Conclusions: Comparison of protease, TIMP-3, and substrate expression showed that in malignant tumors all ADAMTS and TIMP-3 expression levels were significantly raised compared to the substrates studied.
Subject(s)
Ovarian Neoplasms , Humans , Biomarkers, Tumor/metabolism , Gene Expression Regulation, Neoplastic , Neoplasms, Glandular and Epithelial/diagnosis , Tissue Inhibitor of Metalloproteinase-3/metabolism , ADAMTS1 Protein/metabolism , ADAMTS4 Protein/metabolism , Carcinoma, Ovarian EpithelialABSTRACT
Systemic skeletal muscle necrosis induced by crotoxin, the major component of the venom of Crotalus durissus terrificus, was investigated. Mice received an intramuscular injection of crotoxin (0.35mg/kg body weight) into the right tibialis anterior (TA) muscles, which were evaluated 3h, 24h and 3 days later. Control mice were injected with saline. Right and left TAs, gastrocnemius, soleus and right masseter and longissimus dorsi were removed and frozen. Histological sections were stained with Toluidine Blue or incubated for acidic phosphatase reaction. Three and 24h after the injection, signals of muscle fiber injury were found: (a) in the injected TA muscles; (b) in both right and contralateral soleus and red gastrocnemius; and (c) in the masseter muscles. Contralateral TA, longissimus dorsi and white gastrocnemius muscles were not injured. In conclusion, crotoxin induced a systemic and selective muscle injury in muscles or muscle regions composed by oxidative muscle fibers.