Reiss M, Stash E B, Vellucci V F, Zhou Z L
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06517.
Cancer Res. 1991 Dec 1;51(23 Pt 1):6254-62.
Transforming growth factor alpha is an autocrine mitogen for nonneoplastic keratinocytes, which exerts its function by binding to the receptor for epidermal growth factor. In order to determine whether this autocrine pathway is activated in squamous carcinoma cells, we analyzed the production of transforming growth factor alpha as well as the expression and regulation of epidermal growth factor receptors in a panel of human squamous carcinoma cell lines. Immunoreactive transforming growth factor alpha was detectable in squamous carcinoma cells as well as in quiescent nonneoplastic keratinocytes. However, in the absence of exogenous mitogens, only the squamous carcinoma cells secreted the growth factor into the medium, whereas untransformed keratinocytes did not. Each of the squamous carcinoma cell lines expressed significantly greater numbers of cell surface epidermal growth factor receptors than normal keratinocytes. The epidermal growth factor receptor gene was amplified and overexpressed in three of the squamous carcinoma cell lines (A431, CaSki, SqCC/Y1). Two of the squamous carcinoma cell lines (C4-1 and CE-48) displayed a relative inability to down-regulate epidermal growth factor receptors in response to epidermal growth factor. The mechanism of receptor overexpression in the remaining three cell lines (A253, CaLu-1, FaDu) is unexplained. Thus, human squamous carcinoma cell lines frequently exhibit a combination of the constitutive secretion of transforming growth factor alpha and the overexpression of epidermal growth factor receptors. Treatment of these tumor cells with an antibody directed against the ligand-binding domain of the epidermal growth factor receptor inhibited their growth by approximately 50%. These findings suggest that designing strategies to interrupt the transforming growth factor alpha autocrine pathway might lead to new modalities to treat this class of malignant tumors.
转化生长因子α是一种非肿瘤性角质形成细胞的自分泌促有丝分裂原，它通过与表皮生长因子受体结合发挥作用。为了确定这种自分泌途径在鳞状癌细胞中是否被激活，我们分析了一组人鳞状癌细胞系中转化生长因子α的产生以及表皮生长因子受体的表达和调控。在鳞状癌细胞以及静止的非肿瘤性角质形成细胞中均可检测到免疫反应性转化生长因子α。然而，在没有外源性促有丝分裂原的情况下，只有鳞状癌细胞将生长因子分泌到培养基中，而未转化的角质形成细胞则不会。每个鳞状癌细胞系表达的细胞表面表皮生长因子受体数量均显著多于正常角质形成细胞。表皮生长因子受体基因在三个鳞状癌细胞系（A431、CaSki、SqCC/Y1）中发生扩增并过表达。两个鳞状癌细胞系（C4-1和CE-48）相对无法响应表皮生长因子而下调表皮生长因子受体。其余三个细胞系（A253、CaLu-1、FaDu）中受体过表达的机制尚不清楚。因此，人鳞状癌细胞系经常表现出转化生长因子α的组成性分泌和表皮生长因子受体过表达的组合。用针对表皮生长因子受体配体结合域的抗体处理这些肿瘤细胞可使其生长受到约50%的抑制。这些发现表明，设计中断转化生长因子α自分泌途径的策略可能会带来治疗这类恶性肿瘤的新方法。
