ABSTRACT
Few data exist on the prognostic and predictive impact of erb-b2 receptor tyrosine kinase 4 (ERBB4) in ovarian cancer. Thus, we evaluated ERBB4 expression by immunohistochemistry in a tumor microarray consisting of 100 ovarian serous carcinoma specimens (50 complete responses [CRs] and 50 incomplete responses [IRs] to platinum-based therapy), 51 normal tissue controls, and 16 ovarian cancer cell lines. H scores were used to evaluate expression and were semiquantitatively classified into low, intermediate, and high categories. Category frequencies were compared between tumor specimens vs controls using an unpaired t test. Among tumors, category frequencies were compared between CR and IR to chemotherapy. Overall survival (OS) was stratified by category. In total, 74 ovarian serous carcinoma samples (32 CRs and 42 IRs), 28 normal controls, and 16 ovarian cancer cell lines were evaluable. High-level ERBB4 expression was observed at a significantly higher frequency in ovarian serous carcinoma compared with normal control tissue. Among tumor specimens, ERBB4 expression was significantly higher for those with an IR to chemotherapy compared with CR (P = .033). OS was inversely correlated with ERBB4 expression levels. Median rates of OS were 18, 22, and 58 months among high-, intermediate-, and low-expression tumors, respectively. Our results indicate that ERBB4 expression by immunohistochemistry may correlate with chemotherapy-resistant ovarian serous carcinoma and shortened OS.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cystadenocarcinoma, Serous/metabolism , Drug Resistance, Neoplasm , Ovarian Neoplasms/metabolism , Receptor, ErbB-4/metabolism , Aged , Biomarkers, Tumor/metabolism , Carboplatin/administration & dosage , Case-Control Studies , Cell Survival/drug effects , Cisplatin/administration & dosage , Cystadenocarcinoma, Serous/drug therapy , Cystadenocarcinoma, Serous/pathology , Female , Humans , Immunoenzyme Techniques , Neoplasm Staging , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Tumor Cells, CulturedABSTRACT
Cross-presentation is one of the main features of dendritic cells (DCs), which is critically important for the development of spontaneous and therapy-inducible antitumor immune responses. Patients, at early stages of cancer, have normal presence of DCs. However, the difficulties in the development of antitumor responses in patients with low tumor burden raised the question of the mechanisms of DC dysfunction. In this study, we found that, in differentiated DCs, tumor-derived factors blocked the cross-presentation of exogenous Ags without inhibiting the Ag presentation of endogenous protein or peptides. This effect was caused by intracellular accumulation of different types of oxidized neutral lipids: triglycerides, cholesterol esters, and fatty acids. In contrast, the accumulation of nonoxidized lipids did not affect cross-presentation. Oxidized lipids blocked cross-presentation by reducing the expression of peptide-MHC class I complexes on the cell surface. Thus, this study suggests the novel role of oxidized lipids in the regulation of cross-presentation.
Subject(s)
Antigen Presentation/immunology , Cross-Priming/immunology , Dendritic Cells/immunology , Lipids/immunology , Neoplasms/immunology , Acetylcysteine/analogs & derivatives , Acetylcysteine/pharmacology , Animals , Cell Line, Tumor , Cells, Cultured , Culture Media, Conditioned/metabolism , Culture Media, Conditioned/pharmacology , Cysteine Proteinase Inhibitors/pharmacology , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Flow Cytometry , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/immunology , Humans , Interferon-gamma/pharmacology , Lipids/chemistry , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Microscopy, Confocal , Neoplasms/metabolism , Neoplasms/pathology , Ovalbumin/immunology , Oxidation-Reduction , Peptide Fragments/immunologyABSTRACT
The relevance of cysteine metabolism in cancer has gained considerable interest in recent years, largely focusing on its role in generating the antioxidant glutathione. Through metabolomic profiling using a combination of high-throughput liquid and gas chromatography-based mass spectrometry on a total of 69 patient-derived glioma specimens, this report documents the discovery of a parallel pathway involving cysteine catabolism that results in the accumulation of cysteine sulfinic acid (CSA) in glioblastoma. These studies identified CSA to rank as one of the top metabolites differentiating glioblastoma from low-grade glioma. There was strong intratumoral concordance of CSA levels with expression of its biosynthetic enzyme cysteine dioxygenase 1 (CDO1). Studies designed to determine the biologic consequence of this metabolic pathway identified its capacity to inhibit oxidative phosphorylation in glioblastoma cells, which was determined by decreased cellular respiration, decreased ATP production, and increased mitochondrial membrane potential following pathway activation. CSA-induced attenuation of oxidative phosphorylation was attributed to inhibition of the regulatory enzyme pyruvate dehydrogenase. Studies performed in vivo abrogating the CDO1/CSA axis using a lentiviral-mediated short hairpin RNA approach resulted in significant tumor growth inhibition in a glioblastoma mouse model, supporting the potential for this metabolic pathway to serve as a therapeutic target. Collectively, we identified a novel, targetable metabolic pathway involving cysteine catabolism contributing to the growth of aggressive high-grade gliomas. These findings serve as a framework for future investigations designed to more comprehensively determine the clinical application of this metabolic pathway and its contributory role in tumorigenesis.