Thymidine phosphorylase induces angiogenesis in vivo and in vitro: an evaluation of possible mechanisms.
1 Thymidine phosphorylase (TP) is elevated in the plasma of cancer patients, and has been implicated in pathophysiological angiogenesis. However, the downstream signals underlying this implication remain obscure. The purpose of the present study was to examine the effects of TP on the neovascularisation response in vitro and in vivo. 2 Both TP and its catalytic product, 2-deoxy-D-ribose-1-phosphate, and downstream 2-deoxy-D-ribose (2-DDR) promoted endothelial tubulogenesis in vitro, and the regeneration of a wounded monolayer of endothelial cells without exerting any mitogenic effect. In vivo, both TP and 2-DDR promoted the development of functional vasculature into an avascular sponge. A TP inhibitor, 6-amino-5-chlorouracil, was able to partially reverse the effects of TP, but had no effect on the 2-DDR-induced angiogenesis. 3 Enhanced monolayer regeneration was observed with TP-cDNA-transfected bladder carcinoma cells. The transfection of TP-cDNA, however, did not confer any proliferative advantage. The regeneration of TP overexpressing cells was associated with a time-dependent expression of the enzyme haeme-oxygenase (HO-1). 4 The present study demonstrates that both TP and its ribose-sugar metabolites induce angiogenesis by mediating a cohesive interplay between carcinoma and endothelial cells. The induction of HO-1 in TP-transfected cells suggests that it could be a possible downstream signal for the angiogenic effects of TP. Furthermore, reducing sugars have been shown to induce oxidative stress, and ribose could be a possible cause for the upregulation of HO-1, which has been implicated in the release of angiogenic factors. Therefore, we postulate that 2-DDR could be mediating the angiogenic effects of TP possibly through an oxidative stress mechanism and additionally getting integrated in the endothelial metabolic machinery.
Sengupta
Shiladitya
S
Angiogenesis Laboratory, Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD.
Sellers
Lynda A
LA
Matheson
Hugh B
HB
Fan
Tai-Ping D
TP
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003855:Deoxyribose / Q000737:chemistry / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D051547:Heme Oxygenase-1; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D012267:Ribosemonophosphates / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D043925:Angiogenesis Inducing Agents; D008565:Membrane Proteins; D012267:Ribosemonophosphates; C031302:2-deoxyribose 1-phosphate; D003855:Deoxyribose; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D013939:Thymidine Phosphorylase