epidermal-growth-factor and Thymus-Neoplasms

Overexpression and gene amplification of the HER family of receptors and their ligands are important prognostic factors in many solid tumors and treatment targeting these molecules has recently become available. The role of this group of receptors has only rarely been described in thymic epithelial neoplasms and never before in a series of cases consisting exclusively of thymic carcinoma. Twenty-four primary squamous cell carcinomas of the thymus were examined for immunohistochemical expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR (pEGFR), HER2, phosphorylated HER2 (pHER2), HER3, phosphorylated HER3 (pHER3) and their ligands epidermal growth factor (EGF), transforming growth factor-α (TGF-α), amphiregulin and epiregulin. Fluorescence in situ hybridization (FISH) analysis for amplification of the EGFR and HER2 genes was performed including assessment of the copy numbers of EGFR and HER2 gene per cell and the ratio of EGFR and HER2 to centromere 7 and 17, respectively. Significant immunohistochemical expression was observed for EGFR (33.3%), pEGFR (33.3%), HER2 (58.3%), HER3 (45.8%), TGF-α (54.1%), amphiregulin (25.0%) and epiregulin (91.7%). A single case showed HER2 gene amplification by FISH. Increased EGFR and HER2 gene copy numbers were observed in 2 (8.4%) and 18 cases (75%), respectively. Eight cases (33.3%) showed an increased HER2:CEP17 ratio. The results of this study indicate that EGFR and HER2 amplification is a rare event in thymic carcinoma, however, protein expression for HER receptors as well as their ligands is a common finding indicating that targeted therapy directed against these molecules may be considered in the treatment of these tumors.

Topics: Adult; Aged; Aged, 80 and over; Amphiregulin; Disease-Free Survival; DNA Copy Number Variations; EGF Family of Proteins; Epidermal Growth Factor; Epiregulin; ErbB Receptors; Female; Gene Dosage; Glycoproteins; Humans; In Situ Hybridization, Fluorescence; Intercellular Signaling Peptides and Proteins; Kaplan-Meier Estimate; Male; Middle Aged; Thymoma; Thymus Neoplasms; Transforming Growth Factor alpha; Young Adult

Thymic carcinoma is a rare mediastinal malignant tumor, and in many patients, the tumor is detected in an inoperable advanced stage. Even when chemotherapy is administered to such patients, the patients show a poor response. We investigated new biomarkers of therapeutic molecular targets.. This study included 44 patients diagnosed and treated for primary thymic epithelial tumors at Showa University Northern Yokohama Hospital, Showa University Hospital, and Showa University Fujigaoka Hospital from 2003 to 2011. We investigated new biomarkers of therapeutic molecular targets, such as the peroxisome proliferator-activated receptor γ (PPARγ), insulin-like growth factor 1 receptor (IGF1R), epidermal growth factor receptor (EGFR), estrogen receptor (ER), progesterone receptor (PgR), androgen receptor (AR), human epidermal growth factor type 2 (HER2)/neu, CD44, and L-type amino acid transporter 1 (LAT1), in thymic tumors.. Immunohistochemical analysis showed that the PPARγ positivity rate in thymic carcinoma was 32 %, which was significantly higher than that in thymoma (4 %). The IGF1R positivity rate in thymic carcinoma was 73 %, which was significantly higher than that in thymoma (27 %).. Therefore, by examining the expressions of PPARγ and IGF1R, it would be possible to identify therapy-responsive patients and to improve results of thymic carcinoma treatment.

Topics: Adult; Aged; Biomarkers, Tumor; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasms, Glandular and Epithelial; PPAR gamma; Receptor, ErbB-2; Receptors, Androgen; Receptors, Estrogen; Receptors, Progesterone; Thymoma; Thymus Neoplasms

Progression of hematologic malignancies is strongly dependent on bidirectional interactions between tumor cells and stromal cells. Expression of members of the matrix metalloproteinase (MMP) family by stromal cells is a central event during these interactions. However, although several studies have focused on the mechanisms responsible for induction of MMP in stromal cells, the signals that negatively regulate their secretion of in these cells remain largely unknown. Here, we provide evidence that MMP-9 production by stromal cells is suppressed through activation of early growth response protein 1 (EGR-1), thereby inhibiting the growth of thymic lymphoma. We found that EGR-1 expression is induced in stromal cells after contact with lymphoma cells via epidermal growth factor (EGF). Moreover, development of thymic lymphoma was inhibited when induced by lymphoma cells overexpressing EGF compared with control lymphoma cells. Using transgenic mice containing MMP-9 promoter-driven luciferase transgene in its genome, we further demonstrated that EGF/EGR-1 repressed transcriptional activation of the MMP-9 gene by stromal cells. De novo expression of EGR-1 alone by gene transfer or exposure to recombinant human EGF also inhibited MMP-9 expression. Taken together, these results indicate that EGR-1 could be a source of novel targets for therapeutic intervention in lymphoid tumors in which MMP-9 plays a critical role.

Topics: Animals; Cell Line, Tumor; Coculture Techniques; Early Growth Response Protein 1; Endothelial Cells; Enzyme Induction; Epidermal Growth Factor; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, Synthetic; Hemangioendothelioma; Humans; Lymphoma, T-Cell; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Proteins; Promoter Regions, Genetic; Recombinant Fusion Proteins; Specific Pathogen-Free Organisms; Stromal Cells; Thymus Neoplasms; Transcription, Genetic

The mechanisms of ectopic enzyme and enzyme inhibitor-production in neoplastic tissues were investigated. No evidence was obtained to suggest any difference in the structural genes of amylase-producing tumors and normal lymphocytes. mRNA sequence coding for amylase precursor in tumor tissues was identical to that of salivary amylase, suggesting that the amylase in amylase-producing tumors was identical to, or closely resembled the amylase in salivary gland. High incidence of elevation of serum pancreatic secretory trypsin inhibitor (PSTI) was observed in patients with various malignant tumors. PSTI-positive malignant cells were also frequently found in malignant tissues. A comparison of human PSTI mRNA sequence with mouse epidermal growth factor (EGF) mRNA sequence showed that they were 46% homologous. Human PSTI stimulated [3H]thymidine incorporation into DNA in human fibroblasts at concentrations present in human serum.

Topics: Amylases; Animals; Base Sequence; Epidermal Growth Factor; Female; Humans; Lung Neoplasms; Mice; Mice, Nude; Neoplasms; Ovarian Neoplasms; RNA, Messenger; Salivary Glands; Thymoma; Thymus Neoplasms; Trypsin Inhibitor, Kazal Pancreatic; Trypsin Inhibitors