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Background: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.Methods: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.Results: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.Conclusion:These findings suggested that biglycan is a novel TEC marker and a target for anti-angiogenic therapy.

The polyphenol epigallocatechin-3 gallate (EGCG) in green tea suppresses tumor growth by direct action on tumor cells and by inhibition of angiogenesis, but it is not known whether it specifically inhibits tumor angiogenesis. We examined the antiangiogenic effect of EGCG on tumor-associated endothelial cells (TEC), endothelial progenitor cells (EPC), and normal endothelial cells (NEC). EGCG suppressed the migration of TEC and EPC but not NEC. EGCG also inhibited the phosphorylation of Akt in TEC but not in NEC. Furthermore, vascular endothelial growth factor-induced mobilization of EPC into circulation was inhibited by EGCG. MMP-9 in the bone marrow plasma plays key roles in EPC mobilization into circulation. We observed that expression of MMP-9 mRNA was downregulated by EGCG in mouse bone marrow stromal cells. In an in vivo model, EGCG suppressed growth of melanoma and reduced microvessel density. Our study showed that EGCG has selective antiangiogenic effects on TEC and EPC. It is suggested that EGCG could be a promising angiogenesis inhibitor for cancer therapy. T ea is one of the most popular beverages consumed worldwide. Drinking tea, especially green tea, inhibits the growth of several tumors in animal models, including cancers of the skin, lung, esophagus, breast, stomach, small intestine, colon, liver, pancreas, and mammary glands, (1,2) and is associated with a lower incidence of cancer in humans.(1,3,4) The components of green tea responsible for these effects are catechins, which are polyphenols with potent antioxidant capacity that have been shown to inhibit mutation, tumor cell growth, tumor initiation, tumor progression, and the activity of urokinase and MMP, which are crucial for cancer growth.(5-7) Among these catechins, epigallocatechin-3 gallate (EGCG) has the highest antioxidant capacity and is an effective inhibitor of corneal vascularization in vivo. (8) The tumor microenvironment has recently been regarded as a target of cancer chemoprevention because it plays an important role in tumorigenesis and tumor progression.(9) Tumor angiogenesis is one of the key processes within the tumor microenvironment, and controlling this process is a very important strategy for preventing invasive cancers.(10) Many molecules regulating tumor angiogenesis have been identified and characterized recently, including vascular endothelial growth factor (VEGF). (11,12) EGCG has also been shown to inhibit cell proliferation, (13) binding of VEGF to its receptors, (14) phosphorylation of VEGF receptor (VEGFR) 2, (15) MMP activity, (13) and interleukin-8 production (16) in normal endothelial cells such as human umbilical vein endothelial cells.An important concept in tumor angiogenesis is that tumor blood vessels contain endothelial cells that are genetically normal and stable, whereas tumor cells are typically genetically unstable.(17) However, tumor vessels and tumor-associated endothelial cells (TEC) differ from their normal counterparts in many respects. (18)(19)(20) Tumor vessels show structural changes such as ...

Tumor angiogenesis is necessary for solid tumor progression and metastasis. Cyclooxygenase (COX)-2 is known to play an important role in cancer growth and invasion, and it activates the signaling pathways controlling cell proliferation, migration, apoptosis, and angiogenesis. COX-2 is reported to be expressed in many cancer cells. Several studies have reported successful treatment of cancer cells with COX-2 inhibitors (COX-2is). However, the effect of COX-2 inhibition on the tumor endothelium remains to be elucidated. Our study shows that COX-2 is expressed in the vasculature of surgically resected human tumors. To investigate the effects of COX-2 inhibition on the tumor endothelium in vitro, we isolated tumor endothelial cells (TECs) from human melanoma and oral carcinoma xenografts in mice, in which we confirmed that tumor growth was suppressed by inhibiting angiogenesis with the COX-2is NS398. COX-2 mRNA was upregulated in TECs compared to normal endothelial cells (NECs). Cell migration and proliferation were suppressed by NS398 in TECs but not in NECs. The effects of NS398 in vivo were consistent with the in vitro results. The number of CD133 1 /vascular endothelial growth factor receptor-2 1 cells in circulation was significantly suppressed by COX-2 inhibition. In addition, the number of progenitor marker-positive cells decreased in the tumor blood vessels after COX-2i treatment, which suggests that the homing of progenitor cells into the tumor was also blocked. We conclude that NS398 specifically targets both TECs and vascular progenitor cells without affecting NECs.