Stromal LRP1 in Lung Adenocarcinoma Predicts Clinical Outcome
Stromal LRP1 in Lung Adenocarcinoma Predicts Clinical Outcome
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DOI：
10.1158/1078-0432.ccr-10-2385
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发表时间：
2011-04-15
影响因子：
11.5
通讯作者：
Wang, Michael M.
中科院分区：
文献类型：
--
作者：
Meng, He;Chen, Guoan;Wang, Michael M.
目的：LRP1（低密度脂蛋白受体相关蛋白1）是一种广泛表达的受体，可结合多种细胞外配体并参与蛋白质清除。它在多种癌症中表达，但其在肺癌中的作用尚未得到表征。在此，我们研究了 LRP1 与肺癌之间的关系。实验设计：通过多项大型多中心研究测定了肺部肿瘤中的 LRP1 mRNA 水平。 LRP1 蛋白定位通过肺肿瘤微阵列的免疫组织化学分析来确定。将正常成纤维细胞、用LRP1抑制剂RAP（受体相关蛋白）处理的成纤维细胞和Lrp1无效成纤维细胞与3个独立的肺癌细胞系共培养，以研究LRP1对肿瘤细胞增殖的作用。结果：相对于非肿瘤肺组织，肺肿瘤中LRP1 mRNA水平显着降低。在 439 名患者的队列中，肺腺癌中 LRP1 的较低表达与较差的临床结果相关。免疫组织化学分析显示，LRP1主要在94/111肺癌的基质细胞中表达，在癌细胞中发现的蛋白质很少。在测试的 3 种肺癌细胞系（H460、H2347 和 HCC4006 细胞）中观察到小鼠胚胎成纤维细胞 (MEF) 的生长抑制功能； LRP1 抑制剂 RAP 可以阻断生长抑制。成纤维细胞中 Lrp1 的缺失降低了 MEF 细胞抑制肿瘤细胞有丝分裂的能力。在一组腺癌验证中，我们证实了 LRP1 mRNA 和蛋白质水平与良好的临床结果之间存在显着的正相关性。结论：LRP1 表达与改善的肺癌结果相关。从机制上讲，基质LRP1可能非细胞自主地抑制肺肿瘤细胞增殖。临床癌症研究； 17(8)； 2426-33。 (C) 2011 年 AACR。
Purpose: LRP1 (low-density lipoprotein receptor-related protein 1) is a broadly expressed receptor that binds multiple extracellular ligands and participates in protein clearance. It is expressed in numerous cancers, but its role in lung cancer has not been characterized. Here, we investigate the relationship between LRP1 and lung cancer.Experimental Design: LRP1 mRNA levels were determined in lung tumors from several large, multicenter studies. LRP1 protein localization was determined by immunohistochemical analysis of lung tumor microarrays. Normal fibroblasts, fibroblasts treated with the LRP1 inhibitor RAP (receptor-associated protein), and Lrp1 null fibroblasts were cocultured with 3 independent lung cancer cell lines to investigate the role of LRP1 on tumor cell proliferation.Results: LRP1 mRNA levels are significantly decreased in lung tumors relative to nontumorous lung tissue. Lower expression of LRP1 in lung adenocarcinomas correlates with less favorable clinical outcome in a cohort of 439 patients. Immunohistochemical analysis shows that LRP1 is primarily expressed in stromal cells in 94/111 lung cancers, with very little protein found in cancer cells. A growth-suppressive function of mouse embryonic fibroblast (MEF) cells was observed in 3 lung cancer cell lines tested (H460, H2347, and HCC4006 cells); growth suppression was blocked by the LRP1 inhibitor RAP. Lrp1 deletion in fibroblasts reduced the ability of MEF cells to suppress tumor cell mitosis. In a validation set of adenocarcinomas, we confirmed a significant, positive correlation between both LRP1 mRNA and protein levels and favorable clinical outcomes.Conclusions: LRP1 expression is associated with improved lung cancer outcomes. Mechanistically, stromal LRP1 may non-cell autonomously suppress lung tumor cell proliferation. Clin Cancer Res; 17(8); 2426-33. (C) 2011 AACR.