transforming-growth-factor-alpha and Mesothelioma

The majority of malignant pleural mesotheliomas (MPMs) aberrantly express the epidermal growth factor receptor (ErbB1). We examined the efficacy of GW572016 (lapatinib), a dual inhibitor of ErbB1/ErbB2 with a panel of 10 MPM cell lines. Two of the 10 MPM cell lines, H2373 and H2452, underwent G1/S cell cycle arrest and growth inhibition with an IC(50) of 1 muM and 0.8 muM, respectively. There was no relationship between the presence or the amount of ErbB1, phospho-ErbB1, phospho-ErbB2, ErbB3, ErbB4, phospho-Akt, and Akt or the ability of lapatinib to inhibit phospho-ErbB1 in these cell lines compared to those that did not respond to lapatinib. The sensitive cell lines had a time-dependent decrease in phospho-Akt and/or ERK1/2, and an increase in p27 and when treated with lapatinib. The combination of lapatinib with U0126, LY294002 or rapamycin caused greater growth inhibition than either drug alone in the sensitive cell lines while this did not occur in the resistant cell lines. Our findings suggest that ErbB1 alone is a therapeutic target for the minority of mesotheliomas and that combining ErbB1 inhibitors with signal transduction inhibitors in mesothelioma will enhance their effectiveness. Furthermore, combinations of growth factor and signal transduction inhibitors may be needed to inhibit the growth of the majority of MPM cell lines, and therefore patients with MPM.

Topics: Antibiotics, Antineoplastic; Butadienes; Cell Cycle; Chromones; Enzyme Inhibitors; ErbB Receptors; Gene Expression Regulation, Neoplastic; Humans; Lapatinib; Mesothelioma; Mitogen-Activated Protein Kinase 3; Morpholines; Nitriles; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Pleural Neoplasms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Quinazolines; Receptor, ErbB-2; Receptor, ErbB-3; Receptor, ErbB-4; Signal Transduction; Sirolimus; Transforming Growth Factor alpha; Tumor Cells, Cultured

Growth factors such as transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) play an important role in cell proliferation. The immunohistochemical expression of these factors has been extensively studied in malignant tumors including mesothelioma. However, the comparative expression of these growth factors in mesothelioma and reactive mesothelial proliferations has been less well studied.. To evaluate the possible role of TGF-alpha and EGFR in the clinically important distinction between reactive mesothelial proliferations and malignant mesothelioma.. The expression of TGF-alpha and EGFR was studied in 39 cases of mesothelioma and 30 cases of reactive mesothelial proliferations by means of immunohistochemistry.. Fourteen (70%) of 20 reactive mesothelial proliferations tested and 29 (76%) of 38 mesotheliomas tested expressed TGF-alpha. One (3%) of 30 reactive mesothelial proliferations and 17 (45%) of 39 mesotheliomas expressed EGFR.. These results suggest an up-regulation of EGFR in mesothelioma as compared with reactive mesothelial proliferations. This up-regulation further suggests a possible use of EGFR as an adjunct immunohistochemical test in the differential diagnosis of mesothelioma and reactive mesothelial proliferations.

Topics: Biomarkers, Tumor; Cell Division; Diagnosis, Differential; Epithelium; ErbB Receptors; Humans; Immunohistochemistry; Mesothelioma; Transforming Growth Factor alpha

Using ELISAs, we determined the concentrations of transforming growth factor alpha (TGF-alpha), the extracellular domain of the erbB-2 receptor (erbB-2 ECD), and mutant p53 protein in stored serum samples of asbestosis patients with and without cancer and control subjects (without asbestosis or cancer). The percentage of individuals in these three groups with increased serum concentrations of TGF-alpha, erbB-2 ECD, and mutant p53, respectively, were: asbestosis patients with cancer, 36%, 16%, 19%; asbestosis patients without cancer, 38%, 19%, 6%; control subjects, 0%, 5%, 10%. Although differences in serum positivity for these oncoproteins were apparent among these groups, the differences did not achieve statistical significance (P > 0.05). In several of the cancer cases, increased concentrations of TGF-alpha, erbB-2 ECD, and mutant p53 were also detected in the stored serum samples collected years before the clinical diagnosis of disease.

Topics: Asbestosis; Cohort Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lung Neoplasms; Male; Mesothelioma; Oncogene Proteins; Receptor, ErbB-2; Transforming Growth Factor alpha; Tumor Suppressor Protein p53

Although the association between asbestos exposure and mesothelioma development has been established for decades, very little is known regarding the molecular mechanism(s) by which asbestos fibers induce this disease. In this series of experiments, the potential for transforming growth factor alpha (TGF-alpha) to act as an autocrine growth factor in transformed mesothelial cells was examined in rats, a model system frequently used to assess the tumorigenic potential of fibrous particulates. Both asbestos-transformed cells and spontaneously transformed cells expressed functional EGF receptors, although only the asbestos-transformed cells expressed TGF-alpha. Expression of TGF-alpha transcripts was correlated with secretion of picogram amounts of growth factor into conditioned medium by the asbestos-transformed cells. In addition, whereas TGF-alpha inhibited the growth of spontaneously transformed mesothelial cells, it stimulated the growth of asbestos-transformed cells. Neutralizing antibody that recognized TGF-alpha secreted by the asbestos-transformed cells was able to inhibit the growth of these cells. Taken together, these data indicate that TGF-alpha acts as an autocrine growth factor for asbestos-transformed rat mesothelial cells. Therefore, in asbestos-transformed mesothelial cells, altered production and responsiveness to TGF-alpha distinguish these cells from spontaneously transformed mesothelial cells. These data suggest that differences in mesothelioma etiology may be reflected in differences in the molecular alterations present in these tumors.

Topics: Animals; Asbestos, Crocidolite; Blotting, Northern; Cell Division; Cell Line; Cell Line, Transformed; Epidermal Growth Factor; ErbB Receptors; Mesothelioma; Peritoneal Neoplasms; Phosphoproteins; Phosphotyrosine; Radioimmunoassay; Rats; Transforming Growth Factor alpha; Tumor Cells, Cultured; Tyrosine

Malignant cells frequently acquire a certain independency of exogenous growth factors via the coexpression of epidermal growth factor receptor (EGFR) and epidermal growth factor (EGF)-related molecules. In the present study we investigate a possible involvement of EGF-related molecules in the growth of human lung mesothelioma. Four well-characterised cell lines are analysed for their responsiveness to exogenous EGF and transforming growth factor alpha (TGF-alpha) as well as for coexpression of EGFR and EGF/TGF-alpha. Both growth factors are able to stimulate DNA synthesis in three cell lines, although the degree of responsiveness is very variable, but neither EGF nor TGF-alpha has an effect on the cell line ZL34. In contrast, no heterogeneity is observed in the expression of EGFR, which is similarly high in all cell lines. Analysis of cell supernatants reveals that, whereas no EGF is detected, TGF-alpha is released by two cell lines. Furthermore, these two cell lines, ZL5 and ZL34, are shown to express the membrane anchored precursor pro-TGF-alpha. Thus, coexpression of EGFR and TGF-alpha is observed on two mesothelioma cell lines. The potential autocrine mitogenic role of TGF-alpha in these two cell lines was tested using neutralising antibodies against TGF-alpha and EGFR. In ZL5 cells DNA synthesis was not affected by the presence of neutralising antibodies, indicating that an external autocrine mitogenic pathway is not active in these cells. In ZL34 cells, however, the potential autocrine loop could be disrupted, as DNA synthesis was significantly reduced in the presence of neutralising antibodies. This result gives strong evidence for an autocrine role of TGF-alpha in the growth of the mesothelioma cell line ZL34.

Topics: Antibodies, Neoplasm; Cell Division; Cell Membrane; Culture Media; DNA, Neoplasm; Epidermal Growth Factor; ErbB Receptors; Flow Cytometry; Humans; Immunoblotting; Lung Neoplasms; Mesothelioma; Protein Precursors; Transforming Growth Factor alpha; Tumor Cells, Cultured