研究补体激活产物 C4d 作为肺癌的诊断和预后生物标志物。
Investigation of complement activation product c4d as a diagnostic and prognostic biomarker for lung cancer.
机构信息
Affiliations of authors: Division of Oncology, Center for Applied Medical Research, Pamplona, Spain (DA, MJP, LC, JA, LMM, RP); Department of Histology and Pathology (MJP, JA, LMM) and Department of Biochemistry and Genetics (RP) School of Medicine, University of Navarra, Pamplona, Spain; Department of Oncology (JLP), Department of Pathology (MDL), Department of Thoracic Surgery (WT), Department of Pulmonary Medicine (JPdT, JJZ) Clínica Universidad de Navarra, Pamplona, Spain; Thoracic Program, Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN (PPM); Department of Medicine, University of Valencia, Valencia, Spain (CC); Department of Medical Oncology, Hospital General Universitario de Valencia, Valencia, Spain (CC); Molecular Oncology Laboratory, Fundación para la Investigación del Hospital General Universitario de Valencia, Valencia, Spain (EJL).
出版信息
J Natl Cancer Inst. 2013 Sep 18;105(18):1385-93. doi: 10.1093/jnci/djt205. Epub 2013 Aug 12.
BACKGROUND
There is a medical need for diagnostic biomarkers in lung cancer. We evaluated the diagnostic performance of complement activation fragments.
METHODS
We assessed complement activation in four bronchial epithelial and seven lung cancer cell lines. C4d, a degradation product of complement activation, was determined in 90 primary lung tumors; bronchoalveolar lavage supernatants from patients with lung cancer (n = 50) and nonmalignant respiratory diseases (n = 22); and plasma samples from advanced (n = 50) and early lung cancer patients (n = 84) subjects with inflammatory lung diseases (n = 133), and asymptomatic individuals enrolled in a lung cancer computed tomography screening program (n = 190). Two-sided P values were calculated by Mann-Whitney U test.
RESULTS
Lung cancer cells activated the classical complement pathway mediated by C1q binding that was inhibited by phosphomonoesters. Survival was decreased in patients with high C4d deposition in tumors (hazard ratio [HR] = 3.06; 95% confidence interval [CI] = 1.18 to 7.91). C4d levels were increased in bronchoalveolar lavage fluid from lung cancer patients compared with patients with nonmalignant respiratory diseases (0.61 ± 0.87 vs 0.16 ± 0.11 µg/mL; P < .001). C4d levels in plasma samples from lung cancer patients at both advanced and early stages were also increased compared with control subjects (4.13 ± 2.02 vs 1.86 ± 0.95 µg/mL, P < 0.001; 3.18 ± 3.20 vs 1.13 ± 0.69 µg/mL, P < .001, respectively). C4d plasma levels were associated with shorter survival in patients at advanced (HR = 1.59; 95% CI = 0.97 to 2.60) and early stages (HR = 5.57; 95% CI = 1.60 to 19.39). Plasma C4d levels were reduced after surgical removal of lung tumors (P < .001) and were associated with increased lung cancer risk in asymptomatic individuals with (n = 32) or without lung cancer (n = 158) (odds ratio = 4.38; 95% CI = 1.61 to 11.93).
CONCLUSIONS
Complement fragment C4d may serve as a biomarker for early diagnosis and prognosis of lung cancer.
背景
肺癌的诊断需要生物标志物。我们评估了补体激活片段的诊断性能。
方法
我们评估了四种支气管上皮细胞和七种肺癌细胞系中的补体激活。C4d 是补体激活的降解产物，在 90 个原发性肺肿瘤中进行了测定; 来自肺癌患者（n = 50）和非恶性呼吸道疾病患者（n = 22）的支气管肺泡灌洗上清液; 和来自晚期（n = 50）和早期肺癌患者（n = 84）的血浆样本，伴有炎症性肺部疾病（n = 133）和无症状个体参加肺癌计算机断层扫描筛查计划（n = 190）。通过曼-惠特尼 U 检验计算双侧 P 值。
结果
肺癌细胞通过 C1q 结合激活经典补体途径，该途径被磷酸单酯抑制。在肿瘤中 C4d 沉积高的患者中，生存率降低（风险比 [HR] = 3.06; 95%置信区间 [CI] = 1.18 至 7.91）。与非恶性呼吸道疾病患者相比，肺癌患者的支气管肺泡灌洗液中 C4d 水平升高（0.61 ± 0.87 对 0.16 ± 0.11 µg/mL; P <.001）。晚期和早期肺癌患者的血浆样本中 C4d 水平也高于对照组（4.13 ± 2.02 对 1.86 ± 0.95 µg/mL，P < 0.001; 3.18 ± 3.20 对 1.13 ± 0.69 µg/mL，P <.001，分别）。在晚期（HR = 1.59; 95%CI = 0.97 至 2.60）和早期（HR = 5.57; 95%CI = 1.60 至 19.39）阶段，C4d 血浆水平与患者的生存时间较短相关。手术切除肺癌肿瘤后（P <.001），C4d 血浆水平降低，并与无症状个体的肺癌风险增加相关（n = 32）或无肺癌（n = 158）（比值比 = 4.38; 95%CI = 1.61 至 11.93）。
结论
补体片段 C4d 可作为肺癌早期诊断和预后的生物标志物。
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