Recent Advances in Angiogenesis and ... - Bentham Science

More documents

Recommendations

Info

Recent Advances in Angiogenesis and Antiangiogenesis, 2009, 67-79 67 Domenico Ribatti (Ed.) All rights reserved - © 2009 Bentham Science Publishers Ltd. CHAPTER 8 Role of Thymidine Phosphorylase/Platelet-Derived Endothelial Cell Growth Factor in Tumor Progression Sandra Liekens Department of Microbiology and Immunology, Rega Institute for Medical Research, B-3000 Leuven, Belgium Address correspondence to: Dr. Sandra Liekens, Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium; Tel: +32-16-337355; Fax: +32-16-337340; Email: sandra.liekens@rega.kuleuven.be 1. INTRODUCTION Abstract: Thymidine phosphorylase/platelet-derived endothelial cell growth factor (TP/PD- ECGF) has diverse functions within cells, including the regulation of thymidine levels, the mediation of angiogenesis and apoptosis and the activation of prodrugs of the cancer chemotherapeutic agent 5-fluorouracil (5FU). The purpose of this review is to provide an overview of the pro-tumor effects of TP, including the molecular mechanisms of angiogenesis stimulation and apoptosis inhibition by TP. Thymidine phosphorylase (TP) is an important enzyme of the nucleoside salvage pathway [1]. The enzyme was first described and isolated from mammalian tissues more than 50 years ago [2]. TP catalyses the (reversible) phosphorolysis of thymidine and 2’-deoxyuridine to their respective base and -2’-deoxy-D-ribose-1-phosphate (2dR-1P) (Fig. 1). The latter is rapidly converted to 2-deoxy-Dribose (2dR) [3]. In 1987, a novel “endothelial cell growth factor” was purified from human platelets. This protein did not bind heparin, was found to stimulate the incorporation of [ 3 H]thymidine in endothelial cells, 2-deoxy-D-ribose Thymine Salvage pathway but not in fibroblasts, and was therefore named plateletderived endothelial cell growth factor (PD-ECGF) [4]. In 1992, recombinant human PD-ECGF was shown to possess TP activity [5]. Finally, amino acid sequence analysis and gel chromatography revealed that PD- ECGF is identical to TP [6,7]. Thus, the increased uptake of [ 3 H]thymidine in endothelial cells treated with PD-ECGF was not related to any growthpromoting activity, i.e. due to its TP activity, PD-ECGF reduces cellular thymidine pools, resulting in the rapid uptake of a pulse of radiolabeled thymidine [7,8]. PD-ECGF/TP was also found to be identical to gliostatin, a protein isolated from neurofibroma [9]. Gliostatin inhibits the growth of glial tumor cell lines and astrocytes but promotes the survival of cortical TP Thymidine Thymidine DNA degradation Fig. (1). TP catalyzes the conversion of thymidine to thymine and 2-deoxy-D-ribose-1-phosphate. The latter is rapidly dephosphorylated after which it can diffuse out of the cell. Thus, TP removes thymidine from the cytoplasm driving the nucleoside salvage pathway.
68 Recent Advances in Angiogenesis and Antiangiogenesis, 2009 Sandra Liekens neurons [10]. Although the 3 names refer to the same protein, “PD-ECGF” and “TP” are used throughout the literature, whereas the use of “gliostatin” is mainly confined to arthritis and neurological research. 2. ANGIOGENIC ACTIVITY OF TP (Fig. 2) TP has been shown to stimulate (i) chemotaxis of endothelial cells (ECs), (ii) tube formation of ECs in a collagen gel, (iii) outgrowth of vessels from rings of rat aorta and (iv) angiogenesis in several in vivo models, including the CAM assay, gelatin sponges and matrigel plugs implanted in mice and a freezeinjured skin graft model [11-16]. Overexpression of TP in various tumor cell lines did not confer a growth advantage to the cells in vitro [11,13,16,17]. However, transfection of RT112 bladder carcinoma cells with a retroviral vector containing TP cDNA resulted in enhanced regeneration of a wounded monolayer and increased invasion in vitro. [16,18]. Also MKN-45 and YCC-3 gastric cancer cell lines overexpressing TP showed increased adhesion, migration and invasion in vitro [19]. The in vivo effects of TP transfection were found to vary depending on the cell type used. Upon subcutaneous inoculation of Ha-ras-transformed 3T3 cells transfected with TP cDNA, tumors were formed that contained significantly more blood vessels than tumors from mock-transfected cells, but tumor growth itself was not affected by TP [11]. Also, TP overexpression in a rat carcinoma cell line (PROb) had a relatively minor effect on tumor growth and this effect concerned only the initial stages of tumour expansion. However, the number of endothelial cells was consistently higher in TP-expressing tumors than in controls [20]. In contrast, overexpression of TP in MCF-7 breast carcinoma cells markedly increased both the vascular density and the tumor growth rate in vivo [14]. Also TP-overexpressing RT112 cells were characterized by a significantly greater xenograft growth rate than mock-transfected RT112 cells [18]. Nude mice inoculated with TP-overexpressing KB (human epidermoid carcinoma) cells had shorter survival times than those injected with control KB cells, and KB/TP tumors were more invasive than control tumors. [21]. TP also induced invasiveness and metastasis in lung adenocarcinoma [17]. Finally, lung colonization and spontaneous metastasis of A-07 melanoma cells were inhibited by treatment with a neutralizing antibody against TP, indicating that TP might promote lung metastasis of melanomas [22]. Thus, although the effect of TP on tumor growth rate in vivo is cell-type dependent, these studies clearly demonstrate the malignant potential of TP and its capacity to increase tumor vascularization and invasion. The angiogenic activity of TP was inhibited by the TP inhibitor 6-amino-5-chlorouracil and by neutralizing antibodies to TP [11-13]. Moreover, lysates of COS-7 Fig. (2). Various conditions of cellular stress, such as low pH, hypoxia, inflammatory cytokines, radio- and chemotherapy may induce the expression of TP. Degradation of thymidine by TP results in the formation of 2dR-1P, which causes oxidative stress, resulting in the increased expression and secretion of several oxidative stress-response angiogenic factors. 2dR can also leave the cell and induce integrin expression and activation in endothelial cells.
Page 2 and 3: Recent Advances in Angiogenesis and
Page 4 and 5: FOREWORD It has been known for a ve
Page 6 and 7: single proangiogenic protein. Howev
Page 8 and 9: v Vito Pistoia Head, Laboratory of
Page 10 and 11: 2 Recent Advances in Angiogenesis a
Page 12 and 13: 10 Recent Advances in Angiogenesis
Page 16 and 17: The Role of Mesenchymal Stem Cells
Page 22 and 23: Thymus and Angiogenesis Recent Adva
Page 32 and 33: Role of Thymidine Recent Advances i
Page 34 and 35: Role of Stromal Cells Recent Advanc
Page 40 and 41: Tumor Targeting with Transgenic End
Page 44 and 45: Tumor Vascular Disrupting Agents Re
Page 50 and 51: Tumour Vascular Disrupting Agents R
Page 52: Index Recent Advances in Angiogenes

Recent Advances in Angiogenesis and ... - Bentham Science

Create successful ePaper yourself

Delete template?

Save as template?