Thymidine phosphorylase in cancer cells stimulates human endothelial cell migration and invasion by the secretion of angiogenic factors

被引：66

作者：

Bijnsdorp, I. V. ^{[1
]}

Capriotti, F. ^{[1
]}

Kruyt, F. A. E. ^{[1
,2
]}

Losekoot, N. ^{[1
]}

Fukushima, M. ^{[3
]}

Griffioen, A. W. ^{[1
]}

Thijssen, V. L. ^{[1
,4
]}

Peters, G. J. ^{[1
]}

机构：

[1] Vrije Univ Amsterdam Med Ctr, Dept Med Oncol, NL-1007 MB Amsterdam, Netherlands

[2] Univ Groningen, Univ Med Ctr Groningen, Dept Med Oncol, NL-9713 AV Groningen, Netherlands

[3] Taiho Pharmaceut Co Ltd, Tokushima Res Ctr, Tokushima, Japan

[4] Vrije Univ Amsterdam Med Ctr, Dept Radiotherapy, NL-1007 MB Amsterdam, Netherlands

来源：

BRITISH JOURNAL OF CANCER | 2011年 / 104卷 / 07期

关键词：

thymidine phosphorylase; thymidine phosphorylase inhibitor; angiogenesis; deoxyribose; GROWTH FACTOR/THYMIDINE PHOSPHORYLASE; TUMOR-NECROSIS-FACTOR; DIHYDROPYRIMIDINE DEHYDROGENASE; FLUOROPYRIMIDINE SENSITIVITY; GASTRIC-CANCER; COLON-CANCER; EXPRESSION; 2-DEOXY-L-RIBOSE; INHIBITION; 2-DEOXY-D-RIBOSE;

D O I：

10.1038/bjc.2011.74

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

BACKGROUND: Thymidine phosphorylase (TP) is often overexpressed in tumours and has a role in tumour aggressiveness and angiogenesis. Here, we determined whether TP increased tumour invasion and whether TP-expressing cancer cells stimulated angiogenesis. METHODS: Angiogenesis was studied by exposing endothelial cells (HUVECs) to conditioned medium (CM) derived from cancer cells with high (Colo320TP1 = CT-CM, RT112/TP = RT-CM) and no TP expression after which migration (wound-healing-assay) and invasion (transwell-assay) were determined. The involvement of several angiogenic factors were examined by RT-PCR, ELISA and blocking antibodies. RESULTS: Tumour invasion was not dependent on intrinsic TP expression. The CT-CM and RT-CM stimulated HUVEC-migration and invasion by about 15 and 40%, respectively. Inhibition by 10 mu M TPI and 100 mu M L-dR, blocked migration and reduced the invasion by 50-70%. Thymidine phosphorylase activity in HUVECs was increased by CT-CM. Reverse transcription-polymerase chain reaction revealed a higher mRNA expression of bFGF (Colo320TP1), IL-8 (RT112/TP) and TNF-alpha, but not VEGF. Blocking antibodies targeting these factors decreased the migration and invasion that was induced by the CT-CM and RT-CM, except for IL-8 in CT-CM and bFGF in RT-CM. CONCLUSION: In our cell line panels, TP did not increase the tumour invasion, but stimulated the migration and invasion of HUVECs by two different mechanisms. Hence, TP targeting seems to provide a potential additional strategy in the field of anti-angiogenic therapy. British Journal of Cancer (2011) 104, 1185-1192. doi: 10.1038/bjc.2011.74 www.bjcancer.com Published online 8 March 2011 (c) 2011 Cancer Research UK

引用

页码：1185 / 1192

页数：8

共 46 条

[1]

Thymidine phosphorylase: its role in sensitivity and resistance to anticancer drugs [J].

Ackland, SP ;

Peters, GJ .

DRUG RESISTANCE UPDATES, 1999, 2 (04) :205-214

[2]

Microtubule-targeting agents inhibit angiogenesis at subtoxic concentrations, a process associated with inhibition of Rac1 and Cdc42 activity and changes in the endothelial cytoskeleton [J].

Bijman, Marcel N. A. ;

van Nieuw Amerongen, Geerten P. ;

Laurens, Nancy ;

van Hinsbergh, Victor W. M. ;

Boven, Epie .

MOLECULAR CANCER THERAPEUTICS, 2006, 5 (09) :2348-2357

[3]

Accumulation of thymidine-derived sugars in thymidine phosphorylase overexpressing cells [J].

Bijnsdorp, I. V. ;

Azijli, K. ;

Jansen, E. E. ;

Wamelink, M. M. ;

Jakobs, C. ;

Struys, E. A. ;

Fukushima, M. ;

Kruyt, F. A. E. ;

Peters, G. J. .

BIOCHEMICAL PHARMACOLOGY, 2010, 80 (06) :786-792

[4]

Increased Migration by Stimulation of Thymidine Phosphorylase in Endothelial Cells of Different Origin [J].

Bijnsdorp, I. V. ;

Vrijland, K. ;

Vroling, L. ;

Fukushima, M. ;

Peters, G. J. .

NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS, 2010, 29 (4-6) :482-487

[5]

Identification of aspartic acid-203 in human thymidine phosphorylase as an important residue for both catalysis and non-competitive inhibition by the small molecule "crystallization chaperone" 5′-O-tritylinosine (KIN59) [J].

Bronckaers, A. ;

Aguado, L. ;

Negri, A. ;

Camarasa, M. -J. ;

Balzarini, J. ;

Perez-Perez, M. -J. ;

Gago, F. ;

Liekens, S. .

BIOCHEMICAL PHARMACOLOGY, 2009, 78 (03) :231-240

[6]

The Dual Role of Thymidine Phosphorylase in Cancer Development and Chemotherapy [J].

Bronckaers, Annelies ;

Gago, Federico ;

Balzarini, Jan ;

Liekens, Sandra .

MEDICINAL RESEARCH REVIEWS, 2009, 29 (06) :903-953

[7]

Brown NS, 2000, CANCER RES, V60, P6298

[8]

Brown NS, 1998, BIOCHEM J, V334, P1

[9]

Bruin M, 2006, CANC THERAPY, V4, P99

[10]

Targeting the mTOR signaling network in cancer [J].

Chiang, Gary G. ;

Abraham, Robert T. .

TRENDS IN MOLECULAR MEDICINE, 2007, 13 (10) :433-442

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