Abstract
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.
Highlights
Mesothelioma. the tumour derived from mesothelial cells. is mainly associated with exposure to asbestos fibres, as well as to other natural or man-made carcinogenic fibres (Barrett et al, 1989: Merchant, 1990)
Shown to bind to the epidermal growth factor (EGF) receptor (EGFR) in order to stimulate the proliferation of various carcinoma cell lines (Massague, 1990)
For autocrine activity coexpression of Transforming growth factor a (TGF-a) and EGFR is required, a pattern observed in numerous tumour tissues and tumour-derived cell lines, e.g. coexpression of TGF-x and EGF was found in 38% of nonsmall-cell lung cancers (Rusch et al, 1993)
Summary
Mesothelioma. the tumour derived from mesothelial cells. is mainly associated with exposure to asbestos fibres, as well as to other natural or man-made carcinogenic fibres (Barrett et al, 1989: Merchant, 1990). Among a large panel of defined growth factors tested, EGF has been described to exhibit a mitogenic activity on human mesothelioma cell lines (Lauber et al, 1992, 1993). For autocrine activity coexpression of TGF-a and EGFR is required, a pattern observed in numerous tumour tissues and tumour-derived cell lines, e.g. coexpression of TGF-x and EGF was found in 38% of nonsmall-cell lung cancers (Rusch et al, 1993). Several reports indicate that 50-80% of mesothelioma samples bear EGFR (Dazzi et al, 1990; Kayser et al, 1990; Ramael et al, 1991) Considering these facts, we aimed to elucidate the possible autocrine role of the EGF TGF-a -EGFR route in four human lung mesothelioma cell lines
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