Vieau D, Rojas-Miranda A, Verley J M, Lenne F, Bertagna X
Centre de Recherche sur les Maladies Endocriniennes, CHU Cochin-Port-Royal, Paris, France.
Clin Endocrinol (Oxf). 1991 Oct;35(4):319-25. doi: 10.1111/j.1365-2265.1991.tb03543.x.
Bronchial tumours are the most frequent cause of the ectopic ACTH syndrome. Two types of tumours are classically responsible: the relatively benign carcinoids and the highly aggressive small cell carcinomas. Both have neuro-endocrine features and are thought to originate from the endocrine component of the bronchial tree. Our objective was to assess the sensitivity of 7B2 and secretogranin 1 as new biochemical markers of neuro-endocrine differentiation in these tumours in comparison with gastrin releasing peptide.
Tissue concentration of 7B2, secretogranin 1 fragments (GAWK and CCB), gastrin releasing peptide and beta-endorphin were measured in normal human lung (n = 4), bronchial carcinoid tumours with (n = 5) and without (n = 15) the ectopic ACTH syndrome, small cell carcinomas (n = 2), squamous cell carcinomas (n = 11) and adenocarcinomas (n = 6). Molecular weight forms of immunoreactive--ACTH, -GAWK, -gastrin releasing peptide, and -7B2 were also examined using gel exclusion chromatography and Western blot analysis.
We detected 7B2 immunoreactivity in 19 of 22 neuro-endocrine lung tumours (with values ranging from less than 5 to 555 fmol/mg wet weight tissue), CCB immunoreactivity in 20 of 22 tumours with neuro-endocrine features (with values ranging from less than 5 to 19,875 fmol mg wet weight tissue) and gastrin releasing peptide immunoreactivity in 10 of 22 neuro-endocrine lung tumors (with values ranging from less than 5 to 11,132 fmol/mg wet weight tissue). Immunoreactive 7B2 and CCB were detected neither in tumours with non-endocrine features, nor in the four normal lung specimens. Differing molecular weight forms of immunoreactive 7B2 in two bronchial carcinoids associated with the ectopic ACTH syndrome showed a predominant signal corresponding to a molecular weight of 22 kDa; in addition, a second signal of 19 kDa was also present. The differing molecular weight forms of immunoreactive ACTH related peptides in the five tumours responsible for the ectopic ACTH syndrome showed, in addition to ACTH1-39, the constant presence in variable proportions of corticotrophin-like intermediary lobe peptide (or ACTH18-39). The differing molecular weight forms of immunoreactive GAWK showed heterogeneous results with materials eluting at Kav of 0, 0.3 and 0.4 respectively. In the three bronchial carcinoids studied, two immunoreactive gastrin releasing peptide molecular weight forms were always found at Kav of 0.5 and 0.85 corresponding to gastrin releasing peptide and its fragment 14-27 respectively.
Our results show that 7B2 and the two fragments of secretogranin 1 (GAWK and CCB) are the best biochemical markers of neuro-endocrine differentiation in human lung tumours.
支气管肿瘤是异位促肾上腺皮质激素（ACTH）综合征最常见的病因。经典的致病肿瘤有两种：相对良性的类癌和侵袭性很强的小细胞癌。二者均具有神经内分泌特征，被认为起源于支气管树的内分泌成分。我们的目的是评估7B2和分泌粒蛋白1作为这些肿瘤神经内分泌分化新的生化标志物的敏感性，并与胃泌素释放肽作比较。
测定了正常人类肺组织（n = 4）、伴有（n = 5）和不伴有（n = 15）异位ACTH综合征的支气管类癌肿瘤、小细胞癌（n = 2）、鳞状细胞癌（n = 11）和腺癌（n = 6）中7B2、分泌粒蛋白1片段（GAWK和CCB）、胃泌素释放肽及β-内啡肽的组织浓度。还使用凝胶排阻色谱法和蛋白质印迹分析检测了免疫反应性促肾上腺皮质激素（ACTH）、GAWK、胃泌素释放肽和7B2的分子量形式。
在22例神经内分泌性肺肿瘤中的19例检测到7B2免疫反应性（值范围为每毫克湿重组织小于5至555 fmol），在22例具有神经内分泌特征的肿瘤中的20例检测到CCB免疫反应性（值范围为每毫克湿重组织小于5至19,875 fmol），在22例神经内分泌性肺肿瘤中的10例检测到胃泌素释放肽免疫反应性（值范围为每毫克湿重组织小于5至11,132 fmol）。在非内分泌特征的肿瘤以及4例正常肺标本中均未检测到免疫反应性7B2和CCB。与异位ACTH综合征相关的2例支气管类癌中，免疫反应性7B2的不同分子量形式显示主要信号对应于分子量22 kDa；此外，还存在19 kDa的第二个信号。在导致异位ACTH综合征的5例肿瘤中，免疫反应性促肾上腺皮质激素相关肽的不同分子量形式除了ACTH1-39外，还始终以不同比例存在促肾上腺皮质激素样中间叶肽（或ACTH18-39）。免疫反应性GAWK的不同分子量形式显示出异质性结果，洗脱物的Kav分别为0、0.3和0.4。在所研究的3例支气管类癌中，始终在Kav为0.5和0.85处发现两种免疫反应性胃泌素释放肽分子量形式，分别对应于胃泌素释放肽及其片段14-27。
我们的结果表明，7B2和分泌粒蛋白1的两个片段（GAWK和CCB）是人类肺肿瘤神经内分泌分化的最佳生化标志物。
