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Tumor angiogenesis is a complex multistep process regulated by a number of angiogenic factors, one of which is Thymidine Phosphorylase (TP), alternatively known as platelet-derived endothelial cell growth factor (PD-ECGF). TP catalyses the reversible phosphorylation of thymidine to deoxyribose-1-phosphate and thymine. Levels of TP have been shown to be elevated in several human cancers including breast cancer, prostate cancer and melanoma. TP has been shown to increase angiogenesis but the exact mechanisms by which TP promotes angiogenesis are unknown. RNA from human umbilical vein endothelial cells (HUVEC) grown in either the presence or absence of TP was hybridised to a pair of expression array membranes (R&D Systems Ltd), each containing 375 identical angiogenic cDNA PCR products. Subtraction analysis was used to determine differences in expression levels between the two membranes. Allowing for differences in background levels across the membrane we identified differences in expression in 49 angiogenic genes. Real-time RT-PCR confirmed our results in a selection of 5 genes. Each gene was then re-analysed in triplicate in HUVEC. P-selectin showed significantly increased expression at 18 hours following treatment with TP, while nNos showed an increased expression in HUVEC at both 5 and 18 hours. P-selectin is a cell adhesion molecule found on endothelium at the tumor periphery where angiogenesis is most active. In vitro evidence suggests that selectins are involved in capillary morphogenesis, and that ligand binding to the selectins of endothelial cells alters their morphology and function. It has been suggested that TP mediates tumor cell/platelet complexes, which in turn promote metastasis. These complexes are diminished in p-selectin deficient mice, which also have attenuated metastasis formation. Our results suggest a role for TP in the regulation of tumor metastasis through increasing the expression of p-selectin.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]