Cathepsin B, plasminogenactivator-inhibitor (PAI-1) and plasminogenactivator-receptor (uPAR) are prognostic factors for patients with non-small cell lung cancer.
Cathepsin B, plasminogenactivator-inhibitor (PAI-1) and plasminogenactivator-receptor (uPAR) are prognostic factors for patients with non-small cell lung cancer.
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组织蛋白酶 B、纤溶酶原激活物抑制剂 (PAI-1) 和纤溶酶原激活物受体 (uPAR) 是非小细胞肺癌患者的预后因素。
作者：
B. Werle;M. Kotzsch;T. Lah;J. Kos;D. Gabrijelcic‐Geiger;E. Spiess;J. Schirren;W. Ebert;W. Fiehn;T. Luther;V. Magdolen;M. Schmitt;N. Harbeck
为了评估半胱氨酸蛋白酶和丝氨酸蛋白酶及其各自的抑制剂和受体作为NSCLC新的预后因素的可能作用，我们首次研究了147例NSCLC病例中与三种蛋白水解系统相关的10个生物学参数。在肺肿瘤组织和相应的非恶性肺实质的匀浆中测量cath B（C）、cath L（C）、uPA、派-1、uPAR [通过三种不同的测定uPAR（ADI）、uPAR（HD 13）、uPAR（IIIF 10）测量]和TF的活性（cath B（AT）、cath B（A7.5））和蛋白水平。使用合成底物Z-Arg-Arg-AMC，通过荧光测定法测定总cath B活性（cath B（AT））和cath B级分的酶活性（cath B（A7.5）），cath B级分在pH 7.5下稳定且具有活性。酶联免疫吸附法测定cath B（C）、cath L（C）、uPA、派-1、uPAR和TF的浓度。使用三种不同的ELISA形式测定uPAR。导管B（AT）的中位水平（5.1倍），导管B（A7.5）（2.5倍），导管B（C），（8.5倍），导管L（C）（6.6倍），uPA（6.5倍），派-1与肺实质相比，肿瘤组织中uPAR（ADI）（4.2倍）、uPAR（HD 13）（4.0倍）和uPAR（IIIF 10）（2.6倍）的水平更高。原发肿瘤中Cath B（AT）、Cath B（A7.5）和Cath B（C）与淋巴结转移相关。关于组织学，派-1的浓度似乎与NSCLC的组织学细胞类型相关。派-1在大细胞癌> SCC、AC >类癌中表达最高，在其他器官原发肿瘤转移中表达最低。与良好和中等分化的细胞（G1/G2）相比，在低分化的细胞（G3）中仅派-1显著增加。派-1与cath B（AT）、cath B（A7.5）与uPAR（ADI）、uPAR（HD 13）、uPAR（IIIF 10）与uPA显著相关，与TF弱相关，与cath B（C）、cath L（C）无相关性。在单变量分析中观察到cath B（AT）、cath B（C）、派-1、uPAR（ADI）、uPAR（HD 13）和uPAR（IIIF 10）与NSCLC患者总人群的总生存期显著相关。Cath L（C）与不良预后无显著相关性。关于组织学肿瘤类型，只有在鳞状细胞癌患者中，cath B（A7.5）和派-1仍然是重要的预后因素。在多变量生存分析中，只有两个蛋白水解因子，派-1和uPAR（III 101 F），保持显着。总之，在同一患者队列中评价的10个生物学参数中，仅派-1、uPAR（ADI）、uPAR（HD 13）、uPAR（IIIF 10）、cath B（AT）和cath B（C）是NSCLC患者总生存期的预后因素。此外，派-1和uPAR（IIIF 10）增加了独立的预后信息，在非小细胞肺癌的临床和组织形态学因素。
To evaluate the possible role of cysteine proteases and serine proteases, as well as their respective inhibitors and receptors, as new prognostic factors in NSCLC, we examined, for the first time, 10 biological parameters related to three proteolytic systems within a homogeneous collective of 147 cases of NSCLC. Activities (cath B(AT), cath B(A7.5)) and protein levels of cath B(C), cath L(C), uPA, PAI-1, uPAR [measured by three different assays uPAR (ADI), uPAR (HD13), uPAR (IIIF10)] and TF were measured in homogenates of lung tumour tissue and corresponding non-malignant lung parenchyma. Total cath B activity (cath B(AT)) and enzymatic activity of the fraction of cath B, which is stable and active at pH 7.5 (cath B(A7.5)), were determined by a fluorogenic assay using synthetic substrate Z-Arg-Arg-AMC. The concentrations of cath B(C), cath L(C), uPA, PAI-1, uPAR and TF were determined by ELISAs. uPAR was determined using three different ELISA formats. The median levels of cath B(AT) (5.1-fold), cath B(A7.5) (2.5-fold), cath B(C), (8.5-fold), cath L(C) (6.6-fold), uPA (6.5-fold), PAI-1 (4.2-fold), uPAR (ADI) (2.2-fold), uPAR (HD13) (4.0-fold) and uPAR (IIIF10) (2.6-fold) were higher in tumour tissue compared to the lung parenchyma. Cath B(AT), cath B(A7.5) and cath B(C) in primary tumours correlated with lymph node metastases. Regarding histologies, the concentration of PAI-1 seems to be associated with the histological cell types of NSCLC. We found the highest values of PAI-1 in large cell carcinoma > SCC, AC > carcinoid and lowest values in metastases of primary tumours of other organs. Only PAI-1 was significantly increased in poorly-differentiated cells (G3) compared to well- and moderately- differentiated cells (G1/G2). PAI-1 significantly correlated with cath B(AT) and cath B(A7.5) with uPAR (ADI), uPAR (HD13), uPAR (IIIF10) with uPA, and only weakly with TF, but not with cath B(C) and cath L(C). Significant correlations with overall survival in the total population of NSCLC patients were observed in univariate analysis for cath B(AT), cath B(C), PAI-1, uPAR (ADI), uPAR (HD13), and uPAR (IIIF10). Cath L(C) was not significantly associated with poor prognosis. Regarding the histological tumour type, only in patients with squamous cell carcinomas did cath B(A7.5) and PAI-1 remain significant prognostic factors. In multivariate survival analysis only two proteolytic factors, PAI-1 and uPAR (III101F), stayed significant. In conclusion, among 10 biological parameters evaluated within the same cohort of patients, only PAI-1, uPAR (ADI), uPAR (HD13), uPAR (IIIF10), cath B(AT) and cath B(C) are prognostic factors for overall survival of NSCLC patients. Moreover, PAI-1 and uPAR (IIIF10) add independent prognostic information with regard to established clinical and histomorphological factors in NSCLC.
DOI：
10.1073/pnas.95.21.12410
发表时间：
1998-10-13
影响因子：
11.1
作者：
Hughes, SJ;Glover, TW;Hanash, S
通讯作者：
Hanash, S
影响因子：
3.7
作者：
S. Yan;M. Sameni;Bonnie F. Sloane
通讯作者：
S. Yan;M. Sameni;Bonnie F. Sloane
DOI：
--
发表时间：
1972
期刊：
--
影响因子：
--
作者：
D. Cox
通讯作者：
D. Cox