BACKGROUND Angiogenesis is a hallmark of cancer and plays a critical role in lung cancer progression, which involves interactions between cancer cells, endothelial cells and the surrounding microenvironment. However, the gene expression profiles and the changes in the biological phenotype of vascular endothelial cells after interactions with lung cancer cells remain unclear. METHODS An indirect transwell co-culture system was used to survey the interaction between human umbilical vein endothelial cells (HUVECs) and human lung adenocarcinoma CL1-5 cells, as well as to investigate the morphological and molecular changes of HUVECs. The differentially expressed genes (DEGs) in HUVECs after co-culture with cancer cells were identified by microarray. Moreover, a publicly available microarray dataset of 293 non-small-cell lung cancer (NSCLC) patients was employed to evaluate the prognostic power of the gene signatures derived from HUVECs. RESULTS The interaction between HUVECs and lung cancer cells changes the morphology of HUVECs, causing them to have a mesenchymal-like morphology and alter their cytoskeleton organization. Furthermore, after co-culture with lung cancer cells, HUVECs showed increased cell motility and microvessel tube formation ability and a decreased apoptotic percentage. Transcriptomic profiling of HUVECs revealed that many survival-, apoptosis- and angiogenesis-related genes were differentially expressed after interactions with lung cancer cells. Further investigations showed that the PI3K/Akt signalling pathway and COX-2 are involved in endothelial tube formation under the stimulation of lung cancer cells. Moreover, Rac-1 activation might promote endothelial cell motility through the increased formation of lamellipodia and filopodia. The inhibitors of PI3K and COX-2 could reverse the increased tube formation and induce the apoptosis of HUVECs. In addition, the gene signatures derived from the DEGs in HUVECs could predict overall survival and disease-free survival in NSCLC patients and serve as an independent prognostic factor. CONCLUSIONS In this study, we found that cancer cells can promote endothelial cell tube formation and survival, at least in part, through the PI3K/Akt signalling pathway and thus change the microenvironment to benefit tumour growth. The gene signatures from HUVECs are associated with the clinical outcome of NSCLC patients.

中文翻译：

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癌细胞通过激活PI3K / Akt信号通路增加内皮细胞管的形成和存活。

背景技术血管生成是癌症的标志，并且在肺癌进展中起关键作用，其涉及癌细胞，内皮细胞和周围微环境之间的相互作用。然而，与肺癌细胞相互作用后，血管内皮细胞的基因表达谱和生物学表型的变化仍不清楚。方法采用间接transwell共培养系统研究人脐静脉内皮细胞（HUVEC）与人肺腺癌CL1-5细胞之间的相互作用，并研究HUVEC的形态和分子变化。通过微阵列鉴定与癌细胞共培养后HUVEC中的差异表达基因（DEG）。此外，利用公开可用的293位非小细胞肺癌（NSCLC）患者的微阵列数据集来评估HUVEC衍生基因签名的预后能力。结果HUVEC与肺癌细胞之间的相互作用改变了HUVEC的形态，使其具有间充质样形态并改变了其细胞骨架组织。此外，在与肺癌细胞共培养后，HUVEC显示出细胞运动性增强和微血管形成能力增强，且凋亡百分比降低。HUVEC的转录组分析显示，与肺癌细胞相互作用后，许多与生存，凋亡和血管生成相关的基因差异表达。进一步的研究表明，在肺癌细胞的刺激下，PI3K / Akt信号通路和COX-2参与了内皮管的形成。此外，Rac-1激活可能通过增加片状脂蛋白和丝状伪足的形成来促进内皮细胞运动。PI3K和COX-2抑制剂可逆转增加的管形成并诱导HUVEC凋亡。此外，HUVECs中DEGs衍生的基因特征可以预测NSCLC患者的总体生存期和无病生存期，并作为独立的预后因素。结论在这项研究中，我们发现癌细胞可以至少部分通过PI3K / Akt信号通路促进内皮细胞管的形成和存活，从而改变微环境，有利于肿瘤的生长。