Kowalczuk Oksana, Laudanski Jerzy, Laudanski Wojciech, Niklinska Wieslawa Ewa, Kozlowski Miroslaw, Niklinski Jacek
Department of Clinical Molecular Biology, Medical University of Bialystok, 15-269 Bialystok, Poland.
Department of Thoracic Surgery, Medical University of Bialystok, 15-269 Bialystok, Poland.
Oncol Lett. 2018 May;15(5):6752-6762. doi: 10.3892/ol.2018.8159. Epub 2018 Mar 2.
The present study aimed to verify a possibility of ongoing lymphangiogenesis in non-small cell lung cancer (NSCLC) via examination of mRNA levels of a number of lymphangiogenesis-associated genes in tumors. It was hypothesized that transcriptional activation of these genes would occur in tumors that stimulate new lymphatic vessel formation. The study was performed on 140 pairs of fresh-frozen surgical specimens of cancer and unaffected lung tissues derived from NSCLC stage I-IIIA patients. mRNA levels were evaluated with the reverse transcription-quantitative polymerase chain reaction method and expressed as fold change differences between the tumor and normal tissues. Possible associations between expression and patient clinicopathological characteristics and survival were analyzed. In the NSCLC tissue samples, vascular endothelial growth factor (VEGF) C, VEGFD, VEGFR3, VEGFR2, VEGFR1, lymphatic vessel endothelial hyaluronan receptor 1, integrin subunit α 9, FOX2, neuropilin 2, fibroblast growth factor 2 genes were significantly downregulated (P<0.001 for all) compared with matched normal lung tissues, whereas mRNA levels for VEGFA, spleen associated tyrosine kinase, podoplanin, and prospero homeobox 1 genes were similar in both tissues. Neither lymph node status, nor disease pathological stage influenced expression, whereas more profound suppression of gene activities appeared to occur in squamous cell carcinomas compared with adenocarcinomas. The VEGFR1 mRNA expression level was significantly connected with patient survival in the univariate analysis, and was an independent prognostic factor for overall survival in the multivariate Cox's proportional hazards model (HR 2.103; 95% confidence interval: 1.005-4.401; P=0.049). The results support a hypothesis of absence of new lymphatic vessel formation inside growing NSCLC tumor mass, however do not exclude a possibility of lymphangiogenesis in narrow marginal tumor parts.
本研究旨在通过检测肿瘤中多个淋巴管生成相关基因的mRNA水平，验证非小细胞肺癌（NSCLC）中是否存在持续的淋巴管生成。研究假设这些基因的转录激活会发生在刺激新淋巴管形成的肿瘤中。本研究对140对来自I-IIIA期NSCLC患者的癌组织及未受影响的肺组织新鲜冷冻手术标本进行。采用逆转录定量聚合酶链反应法评估mRNA水平，并以肿瘤组织与正常组织之间的倍数变化差异表示。分析了表达与患者临床病理特征及生存之间的可能关联。在NSCLC组织样本中，与匹配的正常肺组织相比，血管内皮生长因子（VEGF）C、VEGFD、VEGFR3、VEGFR2、VEGFR1、淋巴管内皮透明质酸受体1、整合素亚基α9、FOX2、神经纤毛蛋白2、成纤维细胞生长因子2基因均显著下调（所有P<0.001），而VEGFA、脾相关酪氨酸激酶、血小板反应蛋白和prospero同源盒1基因在两种组织中的mRNA水平相似。淋巴结状态和疾病病理分期均不影响表达，而与腺癌相比，鳞状细胞癌中基因活性的抑制似乎更明显。在单因素分析中，VEGFR1 mRNA表达水平与患者生存显著相关，并且在多因素Cox比例风险模型中是总生存的独立预后因素（风险比2.103；95%置信区间：1.005-4.401；P=0.049）。结果支持生长中的NSCLC肿瘤块内不存在新淋巴管形成的假设，但不排除肿瘤边缘狭窄部分存在淋巴管生成的可能性。
