Irigoyen M, Ansó E, Martínez E, Garayoa M, Martínez-Irujo J J, Rouzaut A
Centre for Applied Medical Research, School of Medicine, University of Navarra, Avenida Pío XII, 55, 31008 Pamplona, Spain.
Biochim Biophys Acta. 2007 Jun;1773(6):880-90. doi: 10.1016/j.bbamcr.2007.03.001. Epub 2007 Mar 12.
Recent advances in our understanding of the molecular biology of lymphatic endothelial cells have revealed that these vessels, besides their known function in tissue homeostasis and immunity, constitute conduits for the tumor cells to metastasize. One of the factors that contribute to tumor spread is the acquisition of an angiogenic phenotype as a response to the onset of tumor hypoxia. To our knowledge, little is known about the effects of low oxygen levels on the lymphatic vasculature. Therefore, we used cDNA microarrays to study the transcriptional changes occurring in hypoxia exposed lymphatic endothelial cells. Our analysis was then complemented by functional assays showing that these cells responded with increased attachment to the extracellular matrix, delayed proliferation and production of reactive oxygen species. Differential expression of genes involved in these processes such as NADPH oxidase 4, the tissue inhibitor of metalloproteinase 3, and TGFbeta induced protein I, was found. Hypoxia was also found to increase mRNA levels of the cytokine CXCL-12 and its receptor CXCR4. Moreover, adhesion experiments revealed that hypoxia increased the binding of non-small cell lung carcinoma cells to this endothelium in a CXCR4 dependent way. We thus illustrate the response of lymphatic endothelial cells to hypoxia and suggest targets to study tumor metastasis through these vessels.
我们对淋巴管内皮细胞分子生物学的理解取得了最新进展，这表明这些血管除了在组织稳态和免疫中发挥已知功能外，还构成肿瘤细胞转移的通道。导致肿瘤扩散的因素之一是作为对肿瘤缺氧发生的反应而获得血管生成表型。据我们所知，关于低氧水平对淋巴管系统的影响知之甚少。因此，我们使用cDNA微阵列研究暴露于缺氧环境的淋巴管内皮细胞中发生的转录变化。然后，我们通过功能分析对研究进行补充，结果表明这些细胞对细胞外基质的附着增加、增殖延迟并产生活性氧。我们发现参与这些过程的基因存在差异表达，如NADPH氧化酶4、金属蛋白酶组织抑制剂3和TGFβ诱导蛋白I。还发现缺氧会增加细胞因子CXCL-12及其受体CXCR4的mRNA水平。此外，黏附实验表明，缺氧以CXCR4依赖的方式增加非小细胞肺癌细胞与这种内皮细胞的结合。因此，我们阐述了淋巴管内皮细胞对缺氧的反应，并提出了通过这些血管研究肿瘤转移的靶点。
