Bolon I, Brambilla E, Vandenbunder B, Robert C, Lantuejoul S, Brambilla C
Lung Cancer Research Group, Institut A. Bonniot, La Tronche, Lille, France.
Lab Invest. 1996 Jul;75(1):1-13.
Matrix proteases and the transcription factor c-Ets-1, which regulates in vitro stromelysin 1, collagenase 1, and urokinase type plasminogen activator gene promoters, are frequently expressed in invasive carcinomas. Using in situ hybridization and immunohistochemistry, we analyzed collagenase 1, stromelysins 1 and 3, matrilysin, urokinase type plasminogen activator, and c-Ets-1 gene expression on serial frozen sections of 39 intraepithelial bronchial lesions, including areas of hyperplasia, metaplasia, dysplasia, carcinoma in situ, and corresponding lung carcinomas in 13 patients. In intraepithelial lesions, expression of all matrix proteases was detected in epithelial cells. Conversely, in microinvasive or invasive lesions, a fibroblastic expression was observed. Collagenase 1 and matrilysin were expressed seldomly in intraepithelial lesions and frequently in carcinomas (p = 0.0016 and p < 0.0001, respectively). Stromelysin 1 was expressed inconsistently in 31% of intraepithelial lesions of all grades and in 50% of carcinomas. Stromelysin 3 and urokinase type plasminogen activator were expressed only, but frequently, in preinvasive lesions (dysplasia, carcinoma in situ) and in carcinomas. The expression of stromelysin 3 in fibroblasts started with dysplasia and carcinoma in situ, but was more frequent in invasive than preinvasive lesions (p = 0.0012). c-Ets-1 was more often expressed in carcinomas than in intraepithelial lesions (p < 0.0001) and was always expressed in fibroblasts. Comparing preinvasive lesions adjacent to or at a distance from squamous lung carcinoma, stromelysin 3 epithelial expression was more frequent in preinvasive lesions adjacent to invasive foci than in others (p = 0.036). We conclude that (a) both epithelial expression of matrix proteases in intraepithelial bronchial lesions and their stromal expression in microinvasive and invasive lesions suggest their role in lung tumor development; (b) c-Ets-1 does not act as a transcriptional activator for matrix proteases genes in preinvasion, although it might regulate collagenase 1 gene during lung tumor progression; and (c) matrix proteases might offer new therapeutic targets for chemoprevention of lung cancer.
基质蛋白酶和转录因子c-Ets-1在浸润性癌中经常表达，c-Ets-1可在体外调节基质溶解素1、胶原酶1和尿激酶型纤溶酶原激活剂基因启动子。我们采用原位杂交和免疫组化方法，对13例患者的39个支气管上皮内病变（包括增生、化生、发育异常、原位癌区域）及其相应肺癌的系列冰冻切片进行分析，检测胶原酶1、基质溶解素1和3、基质金属蛋白酶、尿激酶型纤溶酶原激活剂以及c-Ets-1基因的表达情况。在上皮内病变中，所有基质蛋白酶均在上皮细胞中表达。相反，在微浸润或浸润性病变中，则观察到成纤维细胞表达。胶原酶1和基质金属蛋白酶在上皮内病变中很少表达，而在癌组织中经常表达（分别为p = 0.0016和p < 0.0001）。基质溶解素1在所有分级的上皮内病变中有31%表达不一致，在癌组织中有50%表达不一致。基质溶解素3和尿激酶型纤溶酶原激活剂仅在癌前病变（发育异常、原位癌）和癌组织中表达，但表达频繁。成纤维细胞中基质溶解素3的表达始于发育异常和原位癌，但在浸润性病变中比癌前病变中更频繁（p = 0.0012）。c-Ets-1在癌组织中的表达比上皮内病变中更常见（p < 0.0001），并且总是在成纤维细胞中表达。比较与肺鳞状细胞癌相邻或相隔一定距离的癌前病变，基质溶解素3在上皮中的表达在与浸润灶相邻的癌前病变中比在其他病变中更频繁（p = 0.036）。我们得出以下结论：(a) 支气管上皮内病变中基质蛋白酶的上皮表达及其在微浸润和浸润性病变中的基质表达均表明它们在肺肿瘤发生发展中起作用；(b) c-Ets-1在癌前病变中不作为基质蛋白酶基因的转录激活因子，尽管它可能在肺肿瘤进展过程中调节胶原酶1基因；(c) 基质蛋白酶可能为肺癌的化学预防提供新的治疗靶点。
