Tumour blood vessels are gateways for distant metastasis.,Recent studies have revealed that tumour endothelial cells (TECs) demonstrate distinct phenotypes from their normal counterparts.,We have demonstrated that features of TECs are different depending on tumour malignancy, suggesting that TECs communicate with surrounding tumour cells.,However, the contribution of TECs to metastasis has not been elucidated.,Here, we show that TECs actively promote tumour metastasis through a bidirectional interaction between tumour cells and TECs.,Co-implantation of TECs isolated from highly metastatic tumours accelerated lung metastases of low metastatic tumours.,Biglycan, a small leucine-rich repeat proteoglycan secreted from TECs, activated tumour cell migration via nuclear factor-κB and extracellular signal-regulated kinase 1/2.,Biglycan expression was upregulated by DNA demethylation in TECs.,Collectively, our results demonstrate that TECs are altered in their microenvironment and, in turn, instigate tumour cells to metastasize, which is a novel mechanism for tumour metastasis.
We isolated tumour endothelial cells (TECs), demonstrated their abnormalities, compared gene expression profiles of TECs and normal endothelial cells (NECs) by microarray analysis and identified several genes upregulated in TECs.,We focused on the gene encoding biglycan, a small leucine-rich repeat proteoglycan.,No report is available on biglycan expression or function in TECs.,The NEC and TEC were isolated.,We investigated the biglycan expression and function in TECs.,Western blotting analysis of biglycan was performed on sera from cancer patients.,Biglycan expression levels were higher in TECs than in NECs.,Biglycan knockdown inhibited cell migration and caused morphological changes in TECs.,Furthermore, immunostaining revealed strong biglycan expression in vivo in human tumour vessels, as in mouse TECs.,Biglycan was detected in the sera of cancer patients but was hardly detected in those of healthy volunteers.,These findings suggested that biglycan is a novel TEC marker and a target for anti-angiogenic therapy.