ABSTRACT
We have examined for the first time the relationship between the expression of PAPP-A metalloproteinase and insulin-like growth factors (IGF-I, IGF-II, VEGF) and transcription factors (NF-kappaB, HIF-1) playing an important role in pathogenesis of cancer. We also demonstrated a positive association between the level of PAPP-A metalloproteinase and the level of growth (VEGF and IGF-I) and transcription factors (NF-kappaB p50, NF-kappaB p65, HIF-1alpha). The current findings suggest an important role of PAPP-A in regulation of bioavailability of IGF-I, VEGF, activated forms of NF-kappaB, and alpha-subunits of HIF-1 in endometrial tumors.
Subject(s)
Endometrial Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Pregnancy-Associated Plasma Protein-A/metabolism , Endometrial Neoplasms/pathology , Female , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor II/genetics , Insulin-Like Growth Factor II/metabolism , Middle Aged , NF-kappa B/genetics , NF-kappa B/metabolism , Neoplasm Staging , Pregnancy-Associated Plasma Protein-A/genetics , Transcription Factors/biosynthesis , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolismABSTRACT
A mathematical model based on principles of multifactor analysis was developed to predict clinical outcome of endometrial hyperplasia (EH) in patients with metabolic syndrome (80). Seventy-seven factors--anthropometric, clinical, anamnestic, hormono-metabolic, immunohistochemical, etc.--were included. Evaluation of the most informative indices integrated with the discriminative model showed that anthropometric (waist and hip circumference, sagittal diameter, etc.) and clinico-anamnestic (age, age of secondary sexual characters appearance, body weight at birth, suckling pattern, etc.) ones are of similar significance. A profile of hormono-metabolic parameters (cholesterol-low density lipoprotein, leptin, testosterone, progesterone and fasting glucose levels) helped identify a wide range of EH-related disorders in patients with metabolic syndrome. Consistently with the literature data, level of PTEN expression pointed to the presence of this tumor's suppressor in most EH cases which was matched by absence of its expression in endometrial carcinoma. Our model provided high sensitivity (89%) and specificity (82%) in predicting risk of progression in patients with endometrial hyperplasia and metabolic syndrome.
Subject(s)
Endometrial Hyperplasia/complications , Endometrial Hyperplasia/pathology , Endometrial Neoplasms/diagnosis , Endometrial Neoplasms/etiology , Metabolic Syndrome/complications , Models, Theoretical , Biomarkers/blood , Biomarkers, Tumor/analysis , Birth Weight , Body Weight , Cell Transformation, Neoplastic , Disease Progression , Endometrial Hyperplasia/blood , Endometrial Neoplasms/blood , Endometrial Neoplasms/chemistry , Endometrial Neoplasms/pathology , Female , Humans , Immunohistochemistry , Metabolic Syndrome/blood , Middle Aged , PTEN Phosphohydrolase/analysis , Predictive Value of Tests , Risk Assessment , Risk Factors , Sensitivity and Specificity , Waist CircumferenceABSTRACT
The levels of metalloproteinases (MMP-2,-9), their tissue inhibitors (TIMP-1,-2) and extracellular matrix metalloproteinase inducer (EMMPRIN) were studied in tumor tissue and blood serum from patients with head and neck squamous sell carcinoma. Immunohistochemical investigation showed much higher expression of MMP-9 and TIMP-1 in tumor tissue than MMP-2 and TIMP-2. Different expression of the studied parameters (except TIMP-1) in cancer cells and stroma was observed. Enhanced level of MMP-2,-9 and TIMP-2 expression was revealed mainly in fibrocytes, leukocytes and stromal extracellular matrix. Expression of EMMPRIN in tumor cells was higher than in stromal cells. It is possible that carcinoma cells express EMMPRIN to increase MMP production by surrounding cells. Significant decrease of inhibitor expression was observed in cells of carcinomas with N1 grade of metastasis than in tumors without metastasis. Also the decrease in TIMP-1 level was determined in blood serum of patients with metastasis to regional lymph nodes compared with serum of patients without metastasis. Thus, MMP-9 and TIMP-1 play an important role in the development of head and neck squamous sell carcinoma and TIMP-1 level in blood serum and cancer tissues is linked to first grade of regional lymph node metastasis.
Subject(s)
Carcinoma, Squamous Cell/enzymology , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Head and Neck Neoplasms/enzymology , Matrix Metalloproteinase 2/biosynthesis , Matrix Metalloproteinase 9/biosynthesis , Neoplasm Proteins/biosynthesis , Adult , Aged , Basigin/biosynthesis , Carcinoma, Squamous Cell/pathology , Female , Head and Neck Neoplasms/pathology , Humans , Male , Middle Aged , Neoplasm Metastasis , Tissue Inhibitor of Metalloproteinase-1/biosynthesis , Tissue Inhibitor of Metalloproteinase-2/biosynthesisABSTRACT
Levels of matrix metalloproteinase (MMP-2) and endogenous inhibitors (TIMP-1,-2) in tumor and blood serum from patients with squamous-cell laryngeal carcinoma were studied. Immunohistochemical investigation showed much higher MMP-9 expression (76.9%) and TIMP-1 (100%) in tumor tussue than MMP-2 (23.8%) and TIMP-2 (33.3%). Therefore, MMP-9 and TIMP-1 levels in blood serum alone were assayed. TIMP-1 levels in serum from patients were significantly higher than those in healthy subjects (p=0.023). High TIMP-1 levels in blood serum were recorded in patients with stage III laryngeal carcinoma and differed significantly from control (p=0.009). However, no correlation was found between them and MMP concentration in blood serum, on the one hand, and tumor size, on the other. High TIMP-1 levels in blood serum were recorded in patients free from metastasis to regional lymph nodes (124.5+39.5 ng/ml); however, they were lower than in those with such metastases (102.7+10.9 ng/ml) and significantly lower than in healthy subjects (p=0.023). There was a correlation between MMP-9 expression in tumor tissue, on the one hand, and involvement of regional lymph nodes, on the other, (p=0.054). In blood serum from patients showing tumor regression by 75-100% after radiotherapy, TIMP-1 levels were higher than in those with relatively lower response to the same treatment (p=0.072). Hence, assay of TIMP-1 levels in blood serum and MMP-9 concentration in tumor tissue may be used for assessment of tumor processes alongside standard procedures. Moreover, the former may be instrumental in predicting laryngeal response to radiotherapy.
