This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hotchkiss, K. A. Articles by Schwartz, E. L. Search for Related Content PubMed PubMed Citation Articles by Hotchkiss, K. A. Articles by Schwartz, E. L.

Mechanisms by Which Tumor Cells and Monocytes Expressing the Angiogenic Factor Thymidine Phosphorylase Mediate Human Endothelial Cell Migration¹

Departments of Oncology [K. A. H., R. S. K., M. L. L., G. H. Z., E. L. S.] and Medicine (Cardiology) [A. W. A.], Albert Einstein College of Medicine, Bronx, New York 10467

The angiogenic factor thymidine phosphorylase (TP) is highly expressed in many human solid tumors, and the level of its expression is associated with tumor neovascularization, invasiveness, and metastasis and with shorter patient survival time. TP promotes endothelial cell (EC) migration in vitro and angiogenesis in vivo, and these have been linked to its enzymatic activity. The mechanism by which TP stimulates EC migration was investigated using human umbilical vein ECs (HUVECs). TP induced concentration-dependent HUVEC migration, which required a TP gradient and thymidine and which was abrogated by the TP inhibitor CIMU (5-chloro-6(1-imidazolylmethyl)uracil). The chemotactic actions of TP plus thymidine were duplicated by the TP metabolite, 2-deoxyribose-1-phosphate (dR-1-P), and 10-fold more potently by its subsequent metabolite, 2-deoxyribose (2dR). Migration induced by dR-1-P, but not 2dR, was blocked by an alkaline phosphatase inhibitor, suggesting that the actions of dR-1-P first required its conversion to 2dR. In the migration assay, [5'-³H]dThd was metabolized to dR-1-P (96%) and 2dR (3.8%), and a gradient of both metabolites was maintained between the lower and upper chambers over the entire 5-h assay. TP expression in human solid tumors occurs in both tumor epithelial cells and in tumor-associated macrophages. The migration assay was adapted to use TP-transfected carcinoma cells to stimulate HUVEC migration, and they were found to induce more migration than did control vector-transfected cells. Human monocyte cells U937 and THP1, which constitutively expressed high levels of TP, also strongly induced HUVEC migration in the coculture assay. CIMU inhibited tumor-cell and monocyte-induced migration. In contrast, a neutralizing antibody to TP had no effect on cell-stimulated HUVEC migration, even though it completely blocked the migration mediated by purified TP. Thus, the intracellular actions of TP were sufficient to stimulate HUVEC chemotaxis. In contrast to purified TP, when incubated with [5'-³H]-thymidine, cells expressing TP released up to 20-fold more 2dR into the medium than dR-1-P. These studies demonstrate that TP-expressing cells mediate EC migration via the intracellular metabolism of thymidine and subsequent extracellular release of 2dR, which forms a chemotactic gradient.

This article has been cited by other articles:

				J. S. Brockenbrough, J. K. Morihara, S. E. Hawes, J. E. Stern, J. S. Rasey, L. W. Wiens, Q. Feng, and H. Vesselle Thymidine Kinase 1 and Thymidine Phosphorylase Expression in Non-Small-cell Lung Carcinoma in Relation to Angiogenesis and Proliferation J. Histochem. Cytochem., November 1, 2009; 57(11): 1087 - 1097. [Abstract] [Full Text] [PDF]

				G. Solinas, G. Germano, A. Mantovani, and P. Allavena Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation J. Leukoc. Biol., November 1, 2009; 86(5): 1065 - 1073. [Abstract] [Full Text] [PDF]

				H. Lu, R. S. Klein, and E. L. Schwartz Antiangiogenic and Antitumor Activity of 6-(2-Aminoethyl)Amino-5-Chlorouracil, a Novel Small-Molecule Inhibitor of Thymidine Phosphorylase, in Combination with the Vascular Endothelial Growth Factor-Trap Clin. Cancer Res., August 15, 2009; 15(16): 5136 - 5144. [Abstract] [Full Text] [PDF]

				G. Pula, U. Mayr, C. Evans, M. Prokopi, D. S. Vara, X. Yin, Z. Astroulakis, Q. Xiao, J. Hill, Q. Xu, et al. Proteomics Identifies Thymidine Phosphorylase As a Key Regulator of the Angiogenic Potential of Colony-Forming Units and Endothelial Progenitor Cell Cultures Circ. Res., January 2, 2009; 104(1): 32 - 40. [Abstract] [Full Text] [PDF]

				E. J. Yu, Y. Lee, S. Y. Rha, T. S. Kim, H. C. Chung, B. K. Oh, W. I. Yang, S. H. Noh, and H.-C. Jeung Angiogenic Factor Thymidine Phosphorylase Increases Cancer Cell Invasion Activity in Patients with Gastric Adenocarcinoma Mol. Cancer Res., October 1, 2008; 6(10): 1554 - 1566. [Abstract] [Full Text] [PDF]

				S. Liekens, A. Bronckaers, A.-I. Hernandez, E.-M. Priego, E. Casanova, M.-J. Camarasa, M.-J. Perez-Perez, and J. Balzarini 5'-O-Tritylated Nucleoside Derivatives: Inhibition of Thymidine Phosphorylase and Angiogenesis Mol. Pharmacol., August 1, 2006; 70(2): 501 - 509. [Abstract] [Full Text] [PDF]

				S. Liekens, A.-I. Hernandez, D. Ribatti, E. De Clercq, M.-J. Camarasa, M.-J. Perez-Perez, and J. Balzarini The Nucleoside Derivative 5'-O-Trityl-inosine (KIN59) Suppresses Thymidine Phosphorylase-triggered Angiogenesis via a Noncompetitive Mechanism of Action J. Biol. Chem., July 9, 2004; 279(28): 29598 - 29605. [Abstract] [Full Text] [PDF]

				H. Seeliger, M. Guba, G. E. Koehl, A. Doenecke, M. Steinbauer, C. J. Bruns, C. Wagner, E. Frank, K.-W. Jauch, and E. K. Geissler Blockage of 2-Deoxy-D-Ribose-Induced Angiogenesis with Rapamycin Counteracts a Thymidine Phosphorylase-Based Escape Mechanism Available for Colon Cancer under 5-Fluorouracil Therapy Clin. Cancer Res., March 1, 2004; 10(5): 1843 - 1852. [Abstract] [Full Text] [PDF]

				J. M. Mariadason, D. Arango, Q. Shi, A. J. Wilson, G. A. Corner, C. Nicholas, M. J. Aranes, M. Lesser, E. L. Schwartz, and L. H. Augenlicht Gene Expression Profiling-Based Prediction of Response of Colon Carcinoma Cells to 5-Fluorouracil and Camptothecin Cancer Res., December 15, 2003; 63(24): 8791 - 8812. [Abstract] [Full Text] [PDF]

				G. H. Zhu and E. L. Schwartz Expression of the Angiogenic Factor Thymidine Phosphorylase in THP-1 Monocytes: Induction by Autocrine Tumor Necrosis Factor-{alpha} and Inhibition by Aspirin Mol. Pharmacol., November 1, 2003; 64(5): 1251 - 1258. [Abstract] [Full Text] [PDF]

				K. A. Hotchkiss, A. W. Ashton, and E. L. Schwartz Thymidine Phosphorylase and 2-Deoxyribose Stimulate Human Endothelial Cell Migration by Specific Activation of the Integrins {alpha}5{beta}1 and {alpha}V{beta}3 J. Biol. Chem., May 23, 2003; 278(21): 19272 - 19279. [Abstract] [Full Text] [PDF]