Association of immunoreactive hepatocyte growth factor with poor survival in resectable non-small cell lung cancer.-猫眼课题宝

DOI：

发表时间：

1997-02

期刊：

Cancer research

影响因子：

11.2

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

J. Siegfried;L. Weissfeld;P. Singh-Kaw;R. Weyant;J. Testa;R. Landreneau;R. Landreneau

我们之前已经表明，由肺成纤维细胞产生的肝细胞生长因子（HGF）是正常和肿瘤性支气管上皮的有效有丝分裂原和运动原，并且 HGF 受体（c-met 原癌基因蛋白）的表达在人支气管上皮和非小细胞肺癌（NSCLC；P. Singh-Kaw 等人，Am. J.生理学，268：L1012-L1020，1995）。山下等人。据报道，HGF 与乳腺浸润性导管癌的低生存率相关（Cancer Res.，54：1630-1633，1994）。肺癌的预后标志物很少，而且 I 期肺癌的高复发率表明此类患者经常存在无法检测到的肿瘤负荷。需要制定标准来评估这些患者的复发风险。我们现在已经评估了可切除肺部肿瘤中存在的 HGF 是否具有预后意义。在这项研究中，通过定量蛋白质印迹检查了 56 例原发性 NSCLC（主要是腺癌）中 HGF 的存在。这些肿瘤由 34 名 I 期患者、9 名 II 期患者和 13 名接受原发性 NSCLC 根治性切除的 IIIa 期患者的组织组成。通过电泳分离蛋白质并将蛋白质转移至硝酸纤维素膜后对整个肿瘤组织的提取物进行分析。通过与多克隆抗 HGF 抗血清反应来观察免疫反应性 (ir)-HGF，并通过光密度测定法进行定量。肺肿瘤中 ir-HGF 的含量在个体之间差异很大。肿瘤提取物中 ir-HGF 含量的中位数为 15.3 ng/40 microg 肿瘤蛋白；平均 ir-HGF 为 27.2 ng/40 microg 肿瘤蛋白。与没有证据或残留疾病的患者相比，在随访期间复发的患者肿瘤组织中的中位和平均 ir-HGF 均显着较高；所有患者（P = 0.0001）和单独分析的 I 期患者（P = 0.002）都是如此。生存曲线分析表明，高于中位数的 ir-HGF 水平与较差的总生存率相关（P < 0.03）。单变量分析显示三个因素与这组患者的总体生存率较差相关：ir-HGF、肿瘤 (T) 状态（原发肿瘤大小和范围的衡量标准）和年龄。淋巴结 (N) 状态和分期与总生存期仅有轻微相关，很可能是因为研究中的大多数患者处于 I 期。然而，N 状态、分期和 T 状态与无病生存期相关。多变量 Cox 分析表明 ir-HGF、T 状态和年龄独立地对总生存期产生负面影响。 ir-HGF 是一个强有力的独立负性预后指标 (P = 0.0001)，每单位 ir-HGF（ng/40 微克蛋白质）的相对风险为 1.022。这表明，在该组患者中，ir-HGF含量的相对风险随着ir-HGF的增加而持续增加，并且在ir-HGF单位为100或更多时超过10。相比之下，在这组患者中，T 状态大于 1 的相对风险为 4.75，年龄大于 65 岁的相对风险为 3.95。 T 状态大于 1 和 ir-HGF 升高对生存的综合负面影响也非常明显 (P < 0.005)。此外，当患者按分期或 N 状态分层时，ir-HGF 升高会对生存产生负面影响。具有高 ir-HGF 值的 I 期患者的结果比具有低 ir-HGF 值的 II 期或 IIIa 期患者的结果更差。 ir-HGF 升高与可切除 NSCLC 患者群体的不良预后密切相关，并且还确定了预后不良的 I 期患者，表明它可能是早期肺癌患者复发和死亡风险的有用指标。 ir-HGF 升高的影响在 T 状态大于 1 的患者中尤为突出，这表明同时具有两种危险因素的患者

We have shown previously that hepatocyte growth factor (HGF), which is produced by lung fibroblasts, is a potent mitogen and motogen for both normal and neoplastic bronchial epithelium, and that expression of the HGF receptor, the c-met proto-oncogene protein, is uniformly found in the human bronchial epithelium and in non-small cell lung carcinomas (NSCLCs; P. Singh-Kaw et al., Am. J. Physiol., 268: L1012-L1020, 1995). Yamashita et al. have reported an association of HGF with poor survival in invasive ductal carcinoma of the breast (Cancer Res., 54: 1630-1633, 1994). There are few prognostic markers for lung cancer, and the high recurrence rate for stage I lung cancer suggests the frequent presence of undetectable tumor burden in such patients. Criteria are needed to evaluate these patients for risk of recurrence. We have now evaluated whether HGF present in resectable lung tumors has prognostic significance. In this study, 56 primary NSCLCs, mainly adenocarcinomas, were examined for presence of HGF by quantitative Western blot. These tumors consisted of tissue from 34 stage I patients, 9 stage II patients, and 13 stage IIIa patients who underwent curative resection for primary NSCLC. Extracts of whole tumor tissue were analyzed after separation of proteins by electrophoresis and transfer of proteins to nitrocellulose membranes. Immunoreactive (ir)-HGF was visualized by reaction with a polyclonal anti-HGF antiserum and quantitated by densitometry. Lung tumor content of ir-HGF varied widely among individuals. Median ir-HGF content in tumor extracts was 15.3 ng/40 microg of tumor protein; mean ir-HGF was 27.2 ng/40 microg of tumor protein. The median and mean ir-HGF were both significantly higher in tumor tissue from patients who suffered a recurrence during the follow-up period compared with those with no evidence or residual disease; this was true of all patients (P = 0.0001) and stage I patients analyzed separately (P = 0.002). Analysis of survival curves indicated that ir-HGF levels higher than the median were associated with poor overall survival (P < 0.03). Univariate analysis showed three factors related to poor overall survival in this set of patients: ir-HGF, tumor (T) status (a measure of primary tumor size and extent), and age. Nodal (N) status and stage were only marginally related to overall survival, most likely because the majority of the patients in the study were stage I. N status, stage, and T status were related to disease-free survival, however. Multivariate Cox analysis showed that ir-HGF, T status, and age independently had a negative impact on overall survival. ir-HGF was a strong independent negative prognostic indicator (P = 0.0001) with a relative risk of 1.022 per unit of ir-HGF (ng/40 microg of protein). This demonstrates that, in this group of patients, the relative risk of ir-HGF content increased continuously as ir-HGF increased, and exceeded 10 at units of ir-HGF of 100 or more. In comparison, in this group of patients, the relative risk of a T status greater than 1 was 4.75 and that of age greater than 65 was 3.95. The combined negative effect of a T status greater than 1 and elevated ir-HGF on survival was also highly pronounced (P < 0.005). In addition, elevated ir-HGF had a negative impact on survival when patients were stratified by stage or N status. Stage I patients with high ir-HGF values had a worse outcome than stage II or stage IIIa patients with low ir-HGF values. Elevated ir-HGF was strongly associated with poor outcome for resectable NSCLC patients as a group, and also identified stage I patients with poor outcome, indicating that it could be a useful indicator of risk of relapse and death in patients who have early lung cancer. The impact of elevated ir-HGF was especially prominent in patients whose T status was greater than 1, suggesting that patients with both risk factors who are stag

Association of immunoreactive hepatocyte growth factor with poor survival in resectable non-small cell lung cancer.

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