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肿瘤坏死因子及其受体在非小细胞肺癌中的预后意义

Prognostic significance of tumor necrosis factors and their receptors in nonsmall cell lung carcinoma.

作者信息

Tran T A, Kallakury B V, Ambros R A, Ross J S

机构信息

Department of Pathology and Laboratory Medicine, Albany Medical College, New York 12208, USA.

出版信息

Cancer. 1998 Jul 15;83(2):276-82.

PMID:9669810

Abstract

BACKGROUND

In vitro studies have shown an antiproliferative effect of tumor necrosis factor (TNF) against various nonsmall cell lung carcinoma (NSCLC) cell lines. However, clinical trials of combined interleukin-2 and TNF-alpha in patients with advanced NSCLC have demonstrated both conflicting and disappointing results.

METHODS

Immunohistochemical (IHC) staining was performed on formalin fixed, paraffin embedded tissues from 39 bronchogenic adenocarcinomas and 32 squamous cell carcinomas using polyclonal antibodies against TNF-alpha, TNF-beta, TNF-R1, and TNF-R2 proteins. IHC positivity was correlated with tumor stage, grade, and patient survival.

RESULTS

Significant coexpression of TNF-alpha, TNF-beta, TNF-R1, and TNF-R2 was observed in NSCLC (significance range, P < 0.001-0.02). Although immunoreactivity for TNFs remained high in all tumor stages, a loss of TNF-R expression was found in advanced NSCLC (P < 0.006 for TNF-R1 and P < 0.003 for TNF-R2), suggesting down-regulation of TNF-Rs in the process of tumor progression. When all stages were considered together, immunoreactivity for TNF-beta(P < 0.001), TNF-R1, and TNF-R2 (both P < 0.001) significantly correlated with favorable outcome in univariate analysis. However, when stages were studied separately, an association between immunopositivity for TNF-Rs and favorable prognosis was found only in NSCLC without distant metastasis (P < 0.04 and P < 0.005 for TNF-R1 and TNF-R2 in Stage I [according to the American Joint Committee on Cancer staging system] disease, and P < 0.03 and P < 0.02 for TNF-R1 and TNF-R2 in Stage III disease). On multivariate analysis, increased expression of TNF-R1 (P < 0.003) and TNF-R2 (P < 0.001) as well as tumor stage (P < 0.001) independently predicted favorable outcome in patients with NSCLC.

CONCLUSIONS

Although NSCLC exhibits strong coexpression of TNF-alpha, TNF-beta, TNF-R1, and TNF-R2, there is a loss/down-regulation of TNF receptors in high stage tumors. TNF-R1 and TNF-R2 positivity independently predicts favorable outcome in NSCLC, particularly in tumors with no clinically distant metastasis. The current study supports a role for TNFs and their receptors in the evolution and progression of NSCLC.

摘要

背景

体外研究表明肿瘤坏死因子（TNF）对多种非小细胞肺癌（NSCLC）细胞系具有抗增殖作用。然而，晚期NSCLC患者联合使用白细胞介素-2和肿瘤坏死因子-α的临床试验结果相互矛盾且令人失望。

方法

使用抗TNF-α、TNF-β、TNF-R1和TNF-R2蛋白的多克隆抗体，对39例支气管腺癌和32例鳞状细胞癌的福尔马林固定、石蜡包埋组织进行免疫组织化学（IHC）染色。IHC阳性与肿瘤分期、分级及患者生存率相关。

结果

在NSCLC中观察到TNF-α、TNF-β、TNF-R1和TNF-R2显著共表达（显著性范围，P < 0.001 - 0.02）。尽管在所有肿瘤分期中TNF的免疫反应性均保持较高水平，但在晚期NSCLC中发现TNF-R表达缺失（TNF-R1的P < 0.006，TNF-R2的P < 0.003），提示在肿瘤进展过程中TNF-Rs下调。当综合考虑所有分期时，TNF-β（P < 0.001）、TNF-R1和TNF-R2（两者P < 0.001）的免疫反应性在单因素分析中与良好预后显著相关。然而，当分别研究各分期时，仅在无远处转移的NSCLC中发现TNF-Rs免疫阳性与良好预后相关（根据美国癌症联合委员会分期系统，I期疾病中TNF-R1和TNF-R2的P < 0.04和P < 0.005，III期疾病中TNF-R1和TNF-R2的P < 0.03和P < 0.02）。多因素分析显示，TNF-R1（P < 0.003）和TNF-R2（P < 0.001）表达增加以及肿瘤分期（P < 0.001）可独立预测NSCLC患者的良好预后。