Mórocz I A, Schmitter D, Lauber B, Stahel R A
Department of Medicine, University Hospital, Zurich, Switzerland.
Br J Cancer. 1994 Nov;70(5):850-6. doi: 10.1038/bjc.1994.410.
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.
恶性细胞常常通过表皮生长因子受体（EGFR）和表皮生长因子（EGF）相关分子的共表达获得对外源生长因子的某种独立性。在本研究中，我们调查了EGF相关分子在人肺间皮瘤生长中的可能作用。分析了四种特征明确的细胞系对外源EGF和转化生长因子α（TGF-α）的反应性，以及EGFR和EGF/TGF-α的共表达情况。两种生长因子都能够刺激三种细胞系中的DNA合成，尽管反应程度差异很大，但EGF和TGF-α对细胞系ZL34均无影响。相比之下，在EGFR的表达上未观察到异质性，所有细胞系中的表达水平都同样高。对细胞上清液的分析表明，虽然未检测到EGF，但有两种细胞系释放TGF-α。此外，这两种细胞系ZL5和ZL34显示表达膜锚定的前体pro-TGF-α。因此，在两种间皮瘤细胞系中观察到了EGFR和TGF-α的共表达。使用针对TGF-α和EGFR的中和抗体测试了TGF-α在这两种细胞系中的潜在自分泌促有丝分裂作用。在ZL5细胞中，中和抗体的存在不影响DNA合成，表明在这些细胞中外部自分泌促有丝分裂途径不活跃。然而，在ZL34细胞中，潜在的自分泌环路可能被破坏，因为在存在中和抗体的情况下DNA合成显著减少。这一结果有力地证明了TGF-α在间皮瘤细胞系ZL34生长中的自分泌作用。
