Angiogenic Factor Thymidine Phosphorylase Increases Cancer Cell Invasion Activity in Patients with Gastric Adenocarcinoma

Abstract

We investigated the biological role of thymidine phosphorylase (TP), an angiogenic factor, in gastric cancer cell migration and invasion and explored a therapeutic approach for high TP-expressing tumors using TP enzymatic inhibitor (TPI) and rapamycin. We established TP cDNA overexpressing gastric cancer cell lines (MKN-45/TP and YCC-3/TP) and did invasion and adhesion assays with Matrigel-coated transwell membranes. The related signal pathway using recombinant human TP (rhTP), deoxy-D-ribose (D-dRib), and signal pathway inhibitors (wortmannin, LY294002, and rapamycin) was investigated. First, AGS and MKN-1 gastric cancer cell lines showed dose-dependent up-regulation of invasiveness through Matrigel following treatment with rhTP or D-dRib. TP-overexpressing cancer cell lines displayed increased migration and invasion activity, which doubled with rhTP and D-dRib treatment. This activity depended on the enzymatic activity of TP, and TP stimulated the adhesion of cancer cells onto Matrigel and induced actin filament remodeling. Finally, we showed that this activity is related to increased phosphatidylinositol 3-kinase activity in TP-overexpressing cells and that combination treatment with rapamycin and TP enzymatic inhibitor produces an additive effect to abrogate TP-induced invasion. Taken together, TP increases the migration and invasion of gastric cancer cells, especially in TP-expressing cells. Therapies targeting TP might diminish the propensity for invasion and metastasis in gastric cancer. (Mol Cancer Res 2008;6(10):1554 -66)

Comparison of site-specific gene expression levels in primary tumors and synchronous lymph node metastases in advanced gastric cancer

“…TP expression in tumor cells is closely linked to microvascular density, and microvascular density in tumors strongly correlates with VEGF expression [19]. In addition, TP has been shown to convey resistance to hypoxia-induced apoptosis [20] and may also participate in tumor invasion and metastasis in gastric cancer [21][22][23]. However, vascular endothelial growth factor receptor (VEGFR) was not examined in this study.…”

Identification of genes related to a synergistic effect of taxane and suberoylanilide hydroxamic acid combination treatment in gastric cancer cells

“…The SNU series (SNU-1, was obtained from the Korean Cell Line Bank. YCC-1, YCC-2, YCC-3, YCC-6, YCC-7, YCC-9, YCC-10, YCC-11, and YCC-16 cells were established by the Cancer Metastasis Research Center (CMRC, Yonsei University College of Medicine in Seoul, Korea) from advanced gastric cancer patients through isolation from ascites (YCC-1, YCC-2, YCC-3, YCC-6, YCC-7, YCC-9, YCC-10, and YCC-11) or peripheral blood (YCC-16) (Yu et al 2008). Two nonmalignant human fibroblast cell lines (ATCC No.HTB157 and ATCC No.HTB158) were obtained from ATCC (Rockville, Maryland, USA).…”

Effect of 5-Fluorouracil on Thymidine Phosphorylase Activity in Model Experiment

“…High level of TP in the tumor is associated with poor prognosis and decrease in the total survival rate [1,2]. The cells with high expression of TP are characterized by an increase in the migration potential and invasive activity [12]. The inhibition of TP by various drugs (e.g., 5-bromo-6-aminouracil) potentiates apoptosis in cancer cells [8].…”