Ekstrand A J, James C D, Cavenee W K, Seliger B, Pettersson R F, Collins V P
Ludwig Institute for Cancer Research, Stockholm, Sweden.
Cancer Res. 1991 Apr 15;51(8):2164-72.
Anomalies of the epidermal growth factor receptor (EGFR) gene, including amplification, rearrangement, and overexpression, have been reported in malignant human gliomas in vivo. In vitro glioma cell lines coexpress EGFR and at least one of its ligands, transforming growth factor alpha, suggesting the existence of an autocrine growth stimulatory loop. We have studied the tumor tissue from 62 human glioma patients and examined the structure and quantity of the EGFR gene and its transcripts, as well as the quantity of the receptor protein. In addition we have examined the genes and transcripts coding for the pre-pro forms of epidermal growth factor and transforming growth factor alpha, the two endogenous EGFR ligands. EGFR gene amplification was detected in 16 of the 32 malignancy grade IV gliomas (glioblastoma) studied (50%), but only in 1 of 30 gliomas of lesser malignancy grade (I-III). All tumors with an amplified gene overexpressed EGFR mRNA. More than one-half (62.5%) of the glioblastomas with amplified EGFR genes also showed coamplification of rearranged EGFR genes and concomitant expression of aberrant mRNA species. Overexpression, without gene amplification, was observed in some of the low grade gliomas, and aberrant EGFR transcripts were also seen in some cases without gene amplification or detected gene rearrangements. mRNA expression for one or both of the pre-pro forms of the ligands was detected in every tumor studied. Thus, several mechanisms for the activation of the EGFR-mediated growth stimulating pathway are possible in human gliomas in vivo: expression of a structurally altered receptor that may have escaped normal control mechanisms; and/or auto-, juxta-, or paracrine stimulating mechanisms involving coexpression of receptor and ligands, with or without overexpression of the receptor.
在恶性人类胶质瘤体内已报道了表皮生长因子受体（EGFR）基因的异常情况，包括扩增、重排和过表达。体外胶质瘤细胞系共表达EGFR及其至少一种配体——转化生长因子α，提示存在自分泌生长刺激环。我们研究了62例人类胶质瘤患者的肿瘤组织，检测了EGFR基因及其转录本的结构和数量，以及受体蛋白的数量。此外，我们还检测了编码表皮生长因子和转化生长因子α前体形式的基因及其转录本，这两种是内源性EGFR配体。在所研究的32例IV级恶性胶质瘤（胶质母细胞瘤）中，有16例（50%）检测到EGFR基因扩增，但在30例低恶性度（I - III级）胶质瘤中仅1例检测到。所有基因扩增的肿瘤均过表达EGFR mRNA。EGFR基因扩增的胶质母细胞瘤中，超过一半（62.5%）还显示重排的EGFR基因共扩增以及异常mRNA种类的伴随表达。在一些低级别胶质瘤中观察到无基因扩增的过表达，在一些无基因扩增或未检测到基因重排的病例中也发现了异常的EGFR转录本。在所研究的每个肿瘤中均检测到一种或两种配体前体形式的mRNA表达。因此，在人类胶质瘤体内，EGFR介导的生长刺激途径的激活可能有几种机制：表达可能逃避正常调控机制的结构改变的受体；和/或涉及受体和配体共表达的自分泌、旁分泌或邻分泌刺激机制，无论受体是否过表达。
