AUTOCRINE STIMULATION OF A HUMAN LUNG MESOTHELIOMA CELL-LINE IS MEDIATED THROUGH THE TRANSFORMING GROWTH-FACTOR-ALPHA EPIDERMAL GROWTH-FACTOR RECEPTOR MITOGENIC PATHWAY

Malignant cells frequently acquire a certain independency of exogenous growth factors via the coexpression of epidermal growth factor recept or (EGFR) and epidermal growth factor (EGF)-related molecules. In the present study we investigate a possible involvement of EGF-related mol ecules in the growth of human lung mesothelioma. Four well-characteris ed cell lines are analysed for their responsiveness to exogenous EGF a nd transforming growth factor alpha (TGF-alpha) as well as for coexpre ssion of EGFR and EGF/TGF-alpha. Both growth factors are able to stimu late DNA synthesis in three cell lines, although the degree of respons iveness is very variable, but neither EGF nor TGF-alpha has an effect on the cell line ZL34. In contrast, no heterogeneity is observed in th e expression of EGFR, which is similarly high in all cell lines. Analy sis of cell supernatants reveals that, whereas no EGF is detected, TGF -alpha is released by two cell lines. Furthermore, these two cell line s, 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 o f TGF-alpha in these two cell lines was tested using neutralising anti bodies against TGF-alpha and EGFR. In ZL5 cells DNA synthesis was not affected by the presence of neutralising antibodies, indicating that a n external autocrine mitogenic pathway is not active in these cells, I n ZL34 cells, however, the potential autocrine loop could be disrupted , as DNA synthesis was significantly reduced in the presence of neutra lising antibodies. This result gives strong evidence for an autocrine role of TGF-alpha in the growth of the mesothelioma cell line ZL34.