Department of Thoracic Oncology, Thoraxklinik, University of Heidelberg, Amalienstr. 5, 69126 Heidelberg, Germany.
Lung Cancer. 2013 Apr;80(1):19-29. doi: 10.1016/j.lungcan.2012.12.015. Epub 2013 Jan 5.
Cancer-associated fibroblasts (CAF) play a vital role in lung cancer initiation and progression. Although mesenchymal stem cells (MSC) are considered progenitor cells of fibroblasts and show cancer modulating abilities themselves, analyses on their presence and properties in lung cancer are lacking so far.
We performed a comparative molecular and functional analysis of MSC derived from non-small cell lung cancer (NSCLC) and corresponding normal lung tissue (NLT) of a total of 15 patients. MSC were identified and selected according to their mesenchymal multilineage differentiation capability and surface marker profile.
Compared to NLT-MSC, NSCLC-MSC showed accelerated growth kinetics and reduced sensitivity to cisplatin. Karyotyping, comparative genomic hybridization and multiplex fluorescence in situ hybridization revealed no chromosomal aberrations. However, gene expression profiling of NSCLC- and NLT-MSC indicated variable expression of 62 genes involved in proliferation, DNA repair, apoptosis, extracellular matrix synthesis, tissue remodeling and angiogenesis. Differential expression of the selected candidate genes butyrylcholinesterase, clusterin and quiescin Q6 sulfhydryl oxidase 1 was validated by quantitative real-time PCR and, on protein level, by immunohistochemical analyses of original tumor tissue. Upon exposure to tumor cell-conditioned medium or transforming growth factor-β, both, NSCLC-MSC and NLT-MSC acquired expression of α-smooth muscle actin (α-SMA), a major characteristics of CAF.
This study indicates that NSCLC tissue contains MSC with specific molecular and functional properties. These cells might represent a progenitor reservoir for CAF and thus crucially contribute to lung cancer progression.
癌症相关成纤维细胞（CAF）在肺癌的发生和发展中起着至关重要的作用。虽然间充质干细胞（MSC）被认为是成纤维细胞的祖细胞，并且本身具有调节癌症的能力，但迄今为止，关于它们在肺癌中的存在和特性的分析还很缺乏。
我们对总共 15 名患者的非小细胞肺癌（NSCLC）和相应的正常肺组织（NLT）中的 MSC 进行了比较分子和功能分析。MSC 根据其间充质多能分化能力和表面标志物特征进行鉴定和选择。
与 NLT-MSC 相比，NSCLC-MSC 表现出加速的生长动力学和对顺铂的敏感性降低。核型分析、比较基因组杂交和多重荧光原位杂交显示无染色体异常。然而，NSCLC-MSC 和 NLT-MSC 的基因表达谱分析表明，涉及增殖、DNA 修复、凋亡、细胞外基质合成、组织重塑和血管生成的 62 个基因的表达存在差异。定量实时 PCR 验证了候选基因丁酸酯酶、簇蛋白和静止 Q6 巯基氧化酶 1 的差异表达，并通过对原始肿瘤组织的免疫组织化学分析验证了蛋白质水平的差异表达。在暴露于肿瘤细胞条件培养基或转化生长因子-β后，NSCLC-MSC 和 NLT-MSC 均获得了α-平滑肌肌动蛋白（α-SMA）的表达，这是 CAF 的主要特征。
本研究表明，NSCLC 组织中含有具有特定分子和功能特性的 MSC。这些细胞可能代表 CAF 的祖细胞储备库，因此对肺癌的进展至关重要。
