epidermal-growth-factor and Cystadenoma--Serous

While ovarian cancer remains the most lethal gynecological malignancy in the United States, there are no biomarkers available that are able to predict therapeutic responses to ovarian malignancies. One major hurdle in the identification of useful biomarkers has been the ability to obtain enough ovarian cancer cells from primary tissues diagnosed in the early stages of serous carcinomas, the most deadly subtype of ovarian tumor. In order to detect ovarian cancer in a state of hyperproliferation, we analyzed the implications of molecular signaling cascades in the ovarian cancer cell line OVCAR3 in a temporal manner, using a mass-spectrometry-based proteomics approach. OVCAR3 cells were treated with EGF(1), and the time course of cell progression was monitored based on Akt phosphorylation and growth dynamics. EGF-stimulated Akt phosphorylation was detected at 12 h post-treatment, but an effect on proliferation was not observed until 48 h post-exposure. Growth-stimulated cellular lysates were analyzed for protein profiles between treatment groups and across time points using iTRAQ labeling and mass spectrometry. The protein response to EGF treatment was identified via iTRAQ analysis in EGF-stimulated lysates relative to vehicle-treated specimens across the treatment time course. Validation studies were performed on one of the differentially regulated proteins, lysosomal-associated membrane protein 1 (LAMP-1), in human tissue lysates and ovarian tumor tissue sections. Further, tissue microarray analysis was performed to demarcate LAMP-1 expression across different stages of epithelial ovarian cancers. These data support the use of this approach for the efficient identification of tissue-based markers in tumor development related to specific signaling pathways. LAMP-1 is a promising biomarker for studies of the progression of EGF-stimulated ovarian cancers and might be useful in predicting treatment responses involving tyrosine kinase inhibitors or EGF receptor monoclonal antibodies.

Topics: Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Cystadenoma, Serous; Disease Progression; Epidermal Growth Factor; ErbB Receptors; Female; Gene Expression Regulation, Neoplastic; Humans; Lysosomal Membrane Proteins; Neoplasm Grading; Ovarian Neoplasms; Peptides; Phosphatidylinositol 3-Kinases; Phosphorylation; Proteomics; Proto-Oncogene Proteins c-akt; Signal Transduction; Tandem Mass Spectrometry; Tissue Array Analysis

Cyclooxygenase-2 (COX-2) seems to be involved at various steps in the processes of malignant transformation and tumor progression. Investigations have shown that COX-2 overexpression is associated with increased proliferation, reduced apoptosis, and angiogenesis.. Specimens from 125 patients with high-grade, advanced-stage (Stage III-IV) serous ovarian carcinoma were evaluated by immunohistochemistry for COX-2, p53, bcl-2, epidermal growth factor receptor (EGFR), and Her-2/neu expression and for CD34-stained microvessel density (MVD). Statistical analysis was performed to investigate the correlations between COX-2 expression and 1) clinicopathologic characteristics, 2) tumor MVD, and 3) expression of other molecular markers. The effect of COX-2 expression on survival was determined using survival analysis.. Increased COX-2 expression was significantly correlated with tumor MVD (Spearman rank correlation test: r = 0.41; P < 0.001). There was no association observed between COX-2 expression and expression levels of EGFR, Her-2/neu, bcl-2, or p53. Patients who had tumors that showed high COX-2 expression had a worse prognosis compared with patients who had tumors with low expression (death hazard ratio, 2.0; 95% confidence interval, 1.2-3.5; P < 0.001). A multivariate analysis revealed that COX-2 expression was the strongest predictor of survival among the different prognostic factors analyzed.. The current study demonstrated that COX-2 expression was correlated significantly with survival in patients with high-grade, high-stage serous ovarian carcinoma. Expression of COX-2 also was correlated with tumor angiogenesis but not with EGFR, Her-2/neu, or p53 expression. In addition to their prognostic significance, a better understanding of the biology of these molecular changes may help identify new targets for therapy in patients with ovarian carcinoma.

Topics: Adult; Aged; Biomarkers, Tumor; Biopsy, Needle; Cohort Studies; Cystadenoma, Serous; Epidermal Growth Factor; Female; Humans; Immunohistochemistry; Middle Aged; Multivariate Analysis; Neoplasm Staging; Neovascularization, Pathologic; Ovarian Neoplasms; Probability; Prognosis; Prostaglandin-Endoperoxide Synthases; Regression Analysis; Sensitivity and Specificity; Survival Analysis

Elevated levels of the growth factor pS2 protein in the cyst fluids of mucinous cystic tumors correlate with earlier observations using immunohistochemical techniques showing that pS2 protein is expressed by these tumors. The markedly elevated levels of pS2 protein compared to normal plasma values suggest that this growth factor may be important in the pathogenesis of pancreatic mucinous cystic tumors.. Cystic lesions of the pancreas include inflammatory pseudocysts, serous cystadenomas, and mucinous cystic tumors, some of which are malignant. Previous studies using immunohistochemical techniques have shown that virtually all pancreatic mucinous tumors express pS2 protein. pS2 protein is a growth factor that is believed to be important in the normal process of inflammation and repair. We measured pS2 protein and other growth factors in pancreatic cyst fluids to assess their potential pathophysiologic and diagnostic significance.. Levels of pS2 protein were measured in 54 pancreatic cyst fluids by radioimmunoassay. The growth factors, epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), and insulin-like growth factors I and II (IGF-I, IGF-II) were measured in 22 cyst fluids using commercial immunoassays.. Mucinous cysts exhibited significantly higher levels of cyst fluid pS2 protein than nonmucinous lesions, including pseudocysts and serous cystadenomas (median: 78,303 pg/mL; range: 218-361,176 pg/mL vs median: 886 pg/mL; range: 0-14,206 pg/mL; p = 0.0001). The level of pS2 in mucinous tumors was markedly higher than plasma values (median: 392 pg/mL). Levels of pS2 protein in malignant mucinous lesions tended to be higher than those in benign mucinous cysts, but this difference was not statistically significant (median: 88,817 vs 64,350 pg/mL; p = 0.159). Levels of other growth factors, including EGF, TGF-alpha, IGF-I, and IGF-II, did not discriminate among the different cyst types, and the values were within normal plasma ranges.

Topics: Cyst Fluid; Cystadenocarcinoma, Mucinous; Cystadenoma, Mucinous; Cystadenoma, Serous; Epidermal Growth Factor; Humans; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Pancreatic Cyst; Pancreatic Neoplasms; Pancreatic Pseudocyst; Proteins; Transforming Growth Factor alpha; Trefoil Factor-1; Tumor Suppressor Proteins