Rusch V, Klimstra D, Venkatraman E, Pisters P W, Langenfeld J, Dmitrovsky E
Division of Thoracic Surgery, Department of Surgery, Molecular Medicine, Department of Medicine, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Clin Cancer Res. 1997 Apr;3(4):515-22.
The epidermal growth factor receptor (EGFR) and its ligand transforming growth factor (TGF) alpha are hypothesized to form an autocrine growth loop in non-small cell lung cancer (NSCLC) and to play an important role in tumor formation and progression. We studied the association between overexpression of EGFR, TGF-alpha, or both, and overall survival of patients with resectable NSCLC. Overexpression, defined as >20% of tumor cells staining on immunohistochemistry, was examined in 96 tumor samples from consecutive patients having resection of previously untreated, well-staged NSCLC who were then followed prospectively (median follow-up, 20.7 months). The expression of three other ligands for EGFR (epidermal growth factor, cripto, and amphiregulin) was examined by Northern analysis to determine whether they might also contribute to a potential growth stimulatory loop. Overall, survival was calculated by the method of Kaplan and Meier, and prognostic factors were compared using the log-rank test. Overexpression of EGFR only was found in 32% (31 of 96), of TGF-alpha only in 10% (10 of 96), of both EGFR and TGF-alpha in 38% (37 of 96), and of neither in 19% (19 of 96) of tumors. EGFR and TGF-alpha overexpression was observed in all tumor stages and histological types but was most frequent in squamous cell carcinoma. By univariate and multivariate analyses, only tumor stage, not histology or overexpression of EGFR, TGF-alpha, or both, had a significant impact on overall survival. No expression of epidermal growth factor or cripto was observed at the total cellular RNA level of Northern analysis in tumor or benign lung, suggesting that in NSCLC these ligands may not participate in an autocrine growth stimulatory loop with EGFR. Differential overexpression of amphiregulin in malignant versus normal lung was observed, but this expression pattern did not have a prognostic impact. Thus, EGFR and TGF-alpha overexpression is frequent in early-stage NSCLC but is not associated with a survival difference. These findings suggest that this growth factor/receptor loop is more important for lung tumor formation than for tumor progression.
表皮生长因子受体（EGFR）及其配体转化生长因子（TGF）α被认为在非小细胞肺癌（NSCLC）中形成自分泌生长环，并在肿瘤形成和进展中起重要作用。我们研究了EGFR、TGF-α或两者的过表达与可切除NSCLC患者总生存期之间的关联。过表达定义为免疫组化中肿瘤细胞染色>20%，在96例连续接受手术切除的先前未治疗、分期良好的NSCLC患者的肿瘤样本中进行检测，这些患者随后接受前瞻性随访（中位随访时间为20.7个月）。通过Northern分析检测EGFR的其他三种配体（表皮生长因子、cripto和双调蛋白）的表达，以确定它们是否也可能促成潜在的生长刺激环。总体而言，采用Kaplan-Meier方法计算生存期，并使用对数秩检验比较预后因素。仅EGFR过表达在32%（96例中的31例）的肿瘤中发现，仅TGF-α过表达在10%（96例中的10例）的肿瘤中发现，EGFR和TGF-α均过表达在38%（96例中的37例）的肿瘤中发现，两者均不过表达在19%（96例中的19例）的肿瘤中发现。EGFR和TGF-α过表达在所有肿瘤分期和组织学类型中均有观察到，但在鳞状细胞癌中最为常见。通过单因素和多因素分析，只有肿瘤分期，而不是组织学或EGFR、TGF-α或两者的过表达，对总生存期有显著影响。在肿瘤或良性肺组织的Northern分析总细胞RNA水平上未观察到表皮生长因子或cripto的表达，这表明在NSCLC中这些配体可能不参与与EGFR的自分泌生长刺激环。在恶性肺组织与正常肺组织中观察到双调蛋白的差异过表达，但这种表达模式没有预后影响。因此，EGFR和TGF-α过表达在早期NSCLC中很常见，但与生存差异无关。这些发现表明，这种生长因子/受体环对肺肿瘤形成比对肿瘤进展更重要。
