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Human dermal lymphatic endothelial cells stimulated with VEGF-A or VEGF-C for 1h, 4h, 8h and 24h

ABSTRACT: Lymphatic vessel growth and activation, mediated by vascular endothelial growth factor- (VEGF)-C and/or VEGF-A, play an important role in metastatic cancer spread and in chronic inflammation. We aimed to comprehensively identify downstream molecular targets induced by VEGF-A or VEGF-C in lymphatic endothelium. To this end, we treated human dermal lymphatic endothelial cells (LEC) with VEGF-A or VEGF-C for up to 24 hours, followed by a time-series transcriptional profiling using gene microarray technology. We identified a number of genes - many of them not previously known to be involved in lymphangiogenesis - that clustered either as early response genes, transiently induced genes or progressively induced genes. Endothelial specific molecule-1 (ESM-1) was one of the genes that were most potently induced by both VEGF-A and VEGF-C. Keywords: Time course, growth factor comparison

ORGANISM(S): Homo sapiens

PROVIDER: GSE11228 | GEO | 2008/07/25

SECONDARY ACCESSION(S): PRJNA106721

REPOSITORIES: GEO

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Project description:Invasion of lymphatic vessels is a key step in the metastasis of primary tumour cells to draining lymph nodes. Recent evidence indicates that such metastasis can be facilitated by tumour lymphangiogenesis, although it remains unclear whether this is a consequence of increased lymphatic vessel numbers or alteration in the properties of the vessels themselves. Here we have addressed this important question by comparing the RNA profile of normal dermal lymphatic endothelial cells (LEC) with those isolated from tumours of murine T-241/VEGF-C metastatic fibrosarcoma. Our findings reveal significant changes in the expression of some 792 genes in tumour lymphatics (â?¥ 2 fold up/downregulation, p â?¤ 0.05), involving particularly transcripts associated with junctional adhesion, immunomodulation, extracellular matrix and vessel growth/patterning, several of which we have confirmed by RT-PCR and/or immunohistochemistry. Interestingly, this altered phenotype could not be attributed solely to VEGF-C induced lymphoproliferation, as no similar change in gene expression was reported when human LEC were cultured with VEGF-C in vitro. Moreover, we show that a key protein upregulated in the mouse model, namely the tight junction protein Endothelial Cell Specific Adhesion Molecule (ESAM), is similarly upregulated in tumour lymphatic vessels from 2/2 patients with head and neck squamous cell carcinoma and 4/4 patients with aggressive bladder carcinoma. These findings demonstrate a previously unrecognized influence of tumour environment on lymphatic gene expression and identify candidate tumour specific vessel markers that may prove valuable for either prognosis or therapy. Experiment Overall Design: Here we have investigated the invasion of lymphatic vessels as a key step in the metastasis of primary tumour cells to draining lymph nodes by comparing the gene expression profile of normal dermal lymphatic endothelial cells (LEC) with those isolated from tumours of murine T241/VEGF-C/GFP metastatic fibrosarcoma. Three biological replicates were analyzed from each group.

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Human dermal lymphatic endothelial cells stimulated with VEGF-A or VEGF-C for 1h, 4h, 8h and 24h

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